Genomic profiling of post-transplant lymphoproliferative disorders using cell-free DNA

Diagnosing post-transplant lymphoproliferative disorder (PTLD) is challenging and often requires invasive procedures. Analyses of cell-free DNA (cfDNA) isolated from plasma is minimally invasive and highly effective for genomic profiling of tumors. We studied the feasibility of using cfDNA to profile PTLD and explore its potential to serve as a screening tool. We included seventeen patients with monomorphic PTLD after solid organ transplantation in this multi-center observational cohort study. We used low-coverage whole genome sequencing (lcWGS) to detect copy number variations (CNVs) and targeted next-generation sequencing (NGS) to identify Epstein-Barr virus (EBV) DNA load and somatic single nucleotide variants (SNVs) in cfDNA from plasma. Seven out of seventeen (41%) patients had EBV-positive tumors, and 13/17 (76%) had stage IV disease. Nine out of seventeen (56%) patients showed CNVs in cfDNA, with more CNVs in EBV-negative cases. Recurrent gains were detected for 3q, 11q, and 18q. Recurrent losses were observed at 6q. The fraction of EBV reads in cfDNA from EBV-positive patients was 3-log higher compared to controls and EBV-negative patients. 289 SNVs were identified, with a median of 19 per sample. SNV burden correlated significantly with lactate dehydrogenase levels. Similar SNV burdens were observed in EBV-negative and EBV-positive PTLD. The most commonly mutated genes were TP53 and KMT2D (41%), followed by SPEN, TET2 (35%), and ARID1A, IGLL5, and PIM1 (29%), indicating DNA damage response, epigenetic regulation, and B-cell signaling/NFkB pathways as drivers of PTLD. Overall, CNVs were more prevalent in EBV-negative lymphoma, while no difference was observed in the number of SNVs. Our data indicated the potential of analyzing cfDNA as a tool for PTLD screening and response monitoring.</p

Psychological distress among patients with lymphoma: the association with personality and coping strategies

Background: Up to one-quarter of patients with lymphoma experience persisting levels of psychological distress. This study aims to examine the extent to which personality traits and coping strategies, separately and together, are associated with psychological distress among patients with lymphoma, controlling for sociodemographic and clinical characteristics. Methods: A population-based sample of patients with lymphoma, selected from the Netherlands Cancer Registry (NCR), was invited to complete a questionnaire about psychological distress, personality, and coping strategies (Mental Adjustment to Cancer). Sociodemographic and clinical data were retrieved from the NCR. Multivariable linear regression models were constructed to assess the unique variance in psychological distress explained by personality traits and coping strategies separately and together. Results: A total of 456 patients completed the questionnaire (51%), the average age was 65 years, 64% were male, and 17% reported psychological distress. Of sociodemographic and clinical characteristics, comorbidity (β = .14, P < .001) and age (β = −.10, P = .03) were independently associated with psychological distress. In addition, of personality traits, only neuroticism was related to psychological distress (neuroticism, β = .43, P < .001). Furthermore, the coping styles anxious preoccupation (β = .12, P = .01) and helplessness/hopelessness (β = .30, P < .001) were associated with more psychological distress, whereas avoidance was associated to less psychological distress (β = −.09, P = .01). Conclusions: In conclusion, besides comorbidity and age, personality traits—in particular neuroticism—and the coping strategies helplessness/hopelessness, anxious preoccupation, and avoidance were significantly independently associated with psychological distress. Unlike personality, coping strategies are considered to be changeable and could be targeted by interventions such as cognitive behavioral therapy

Psychological distress among patients with lymphoma: the association with personality and coping strategies

Background: Up to one-quarter of patients with lymphoma experience persisting levels of psychological distress. This study aims to examine the extent to which personality traits and coping strategies, separately and together, are associated with psychological distress among patients with lymphoma, controlling for sociodemographic and clinical characteristics. Methods: A population-based sample of patients with lymphoma, selected from the Netherlands Cancer Registry (NCR), was invited to complete a questionnaire about psychological distress, personality, and coping strategies (Mental Adjustment to Cancer). Sociodemographic and clinical data were retrieved from the NCR. Multivariable linear regression models were constructed to assess the unique variance in psychological distress explained by personality traits and coping strategies separately and together. Results: A total of 456 patients completed the questionnaire (51%), the average age was 65 years, 64% were male, and 17% reported psychological distress. Of sociodemographic and clinical characteristics, comorbidity (β = .14, P < .001) and age (β = −.10, P = .03) were independently associated with psychological distress. In addition, of personality traits, only neuroticism was related to psychological distress (neuroticism, β = .43, P < .001). Furthermore, the coping styles anxious preoccupation (β = .12, P = .01) and helplessness/hopelessness (β = .30, P < .001) were associated with more psychological distress, whereas avoidance was associated to less psychological distress (β = −.09, P = .01). Conclusions: In conclusion, besides comorbidity and age, personality traits—in particular neuroticism—and the coping strategies helplessness/hopelessness, anxious preoccupation, and avoidance were significantly independently associated with psychological distress. Unlike personality, coping strategies are considered to be changeable and could be targeted by interventions such as cognitive behavioral therapy

Extent of radiological response does not reflect survival in primary central nervous system lymphoma

Background. In primary central nervous system lymphoma (PCNSL), small enhancing lesions can persist after treatment. It is unknown whether a difference in response category (complete response [CR], complete response unconfirmed [CRu], or partial response [PR]) reflects survival. We aimed to determine the value of a central radiology review on response assessment and whether the extent of response influenced progression-free and/or overall survival. Methods. All patients in the HOVON 105/ALLG NHL 24 study with at least a baseline MRI and one MRI made for response evaluation available for central review were included. Tumor measurements were done by 2 independent central reviewers, disagreements were adjudicated by a third reviewer. Crude agreement and interobserver agreement (Cohen's kappa) were calculated. Differences in progression-free and overall survival between different categories of response at the end-of-protocol-treatment were assessed by the log-rank test in a landmark survival-analysis. Results. Agreement between the central reviewers was 61.7% and between local and central response assessment was 63.0%. Cohen's kappa's, which corrects for expected agreement, were 0.44 and 0.46 (moderate), respectively. Progression agreement or not was 93.3% (kappa 0.87) between local and central response assessment. There were no significant differences in progression-free and overall survival between patients with CR, CRu, or PR at the endof- protocol-treatment, according to both local and central response assessment

Rituximab in patients with primary CNS lymphoma (HOVON 105/ALLG NHL 24) : a randomised, open-label, phase 3 intergroup study

Background: The prognosis for primary CNS lymphoma has improved with the use of high-dose methotrexate-based chemotherapy, but patient outcomes remain poor. Rituximab, a chimeric monoclonal antibody that targets the CD20 cell surface protein, has substantial activity in systemic CD20-positive diffuse large B-cell lymphoma, but its efficacy in primary CNS lymphoma is unknown and low penetration of the large rituximab molecule through the blood–brain barrier could limit its effect. We aimed to investigate the addition of rituximab to a high-dose methotrexate-based chemotherapy regimen in patients with newly diagnosed primary CNS lymphoma. Methods: This intergroup, multicentre, open-label, randomised phase 3 study was done at 23 hospitals in the Netherlands, Australia, and New Zealand. Non-immunocompromised patients aged 18–70 years with newly diagnosed primary CNS lymphoma were randomly assigned (1:1) to receive methotrexate-based chemotherapy with or without intravenous rituximab. We used a web-based randomisation system with stratification by centre, age, and Eastern Cooperative Oncology Group–WHO performance status, and a minimisation procedure. All group assignment was open label and neither investigators nor patients were masked to allocation. All patients were treated with two 28-day cycles of induction chemotherapy, consisting of intravenous methotrexate 3 g per m2 on days 1 and 15, intravenous carmustine 100 mg per m2 on day 4, intravenous teniposide 100 mg per m2 on days 2 and 3, and oral prednisone 60 mg per m2 on days 1–5, with (R-MBVP) or without (MBVP) intravenous rituximab 375 mg per m2 on days 0, 7, 14, and 21 in cycle one and days 0 and 14 in cycle two. Patients with response at the end of induction subsequently received high-dose cytarabine and, in patients aged 60 years or younger, low-dose whole-brain radiotherapy. The primary endpoint was event-free survival, with events defined as not reaching complete response or complete response unconfirmed at the end of treatment, or progression or death after response; analysis was adjusted for age and performance score. Patients were analysed on a modified intention-to-treat basis. This trial is registered with the Nederlands Trial Register, number NTR2427, and the Australian New Zealand Clinical Trials Registry, number ACTRN12610000908033. The trial was closed on May 27, 2016, after achieving complete accrual, and follow-up is ongoing. Findings: Between Aug 3, 2010, and May 27, 2016, we recruited 200 patients (109 men and 91 women; median age was 61 years [IQR 55–67]). We randomly assigned 100 patients to MBVP and 99 patients to R-MBVP. One patient was randomly assigned to the R-MBVP group but found to be ineligible because of an incorrect diagnosis and was excluded from all analyses. After a median follow-up of 32·9 months (IQR 23·9–51·5), 98 patients had had an event (51 in the MBVP group and 47 in the R-MBVP group), of whom 79 had died (41 in the MBVP group and 38 in the R-MBVP group). Event-free survival at 1 year was 49% (95% CI 39–58) in the MBVP group (no rituximab) and 52% (42–61) in the R-MBVP group (with rituximab; hazard ratio 1·00, 95% CI 0·70–1·43, p=0·99). Grade 3 or 4 adverse events occurred in 58 (58%) patients in the MBVP group and 63 (64%) patients in the R-MBVP group, with infections (24 [24%] patients receiving MBVP vs 21 [21%] patients receiving R-MBVP), haematological toxicity (15 [15%] vs 12 [12%]), and nervous system disorders (ten [10%] vs 15 [15%]) being the most common. Life-threatening or fatal serious adverse events occurred in 12 (12%) patients in the MBVP group and ten (10%) patients in the R-MBVP group, and five (5%) patients in the MBVP group and three (3%) in the R-MBVP group died from treatment-related causes. Interpretation: We found no clear benefit of addition of rituximab to methotrexate, carmustine, teniposide, and prednisone chemotherapy in primary CNS lymphoma. Therefore, the results of this study do not support the use of rituximab as a component of standard treatment in primary CNS lymphoma. Funding: Roche, the Dutch Cancer Society, and Stichting STOPhersentumoren

An infrastructure for service oriented sensor networks

Emerging wireless technologies enable ubiquitous access to networked services. Integration of wireless technologies into sensor and actuator nodes provides the means for remote access and control. However, ad hoc deployment of nodes complicates the process of finding, selecting and sing these in a meaningful way. The use of a service discovery framework enables nodes to present themselves and the resources they hold. In this paper, we review the applicability of a number of well-known service discovery protocols in the context of networked nodes. Multicast DNS and Service Discovery (mDNS-SD) stands out with its auto-configuration, distributed architecture,sharing of resources, and wide area access. For wireless battery operated and resource constrained nodes, we seek to integrate SD and power management techniques. This leads us to a standards based infrastructure for service oriented sensor networks where; 1) nodes collaborate in an ad hoc fashion by using SD techniques to discover (and announce) resources locally and over the public Internet, 2) nodes preserve power through aggressive utilization of low power (sleep) modes, while yet being reachable for clients according to defined schemas, and 3) clients may access and configure nodes, and (if possible) access sleeping nodes by implicit wake-up procedures. To demonstrate the proposed infrastructure a complete experimental setup has been devised featuring; Bluetooth enabled nodes, lightweight implementations of mDNS-SD and communication stacks, Internet access through cellular/wired gateways, together with a public DNS server. Our experiments verify that mDNS-SD can be effectively deployed on small wireless sensor and actuator nodes and provides the basis of a service oriented infrastructure for low power sensor networks.Validerad; 2006; 20061206 (jench)</p