CREBBP histone acetyltransferase domain mutations predict response to mTOR inhibition in relapsed/refractory follicular lymphoma.

Despite the clinical and molecular heterogeneity of follicular lymphoma (FL), there remains a lack of biomarker-directed therapeutic approaches in routine clinical practice, with the notable exception of the EZH2 inhibitor tazemetostat in EZH2-mutant FL. Here we examined whether gene mutation status predicts response to clinical mTOR inhibitors (mTORi) in FL, by performing targeted mutational profiling of biopsies from 21 relapsed/refractory FL patients treated with mTORi everolimus or temsirolimus within clinical trials. We observed an enrichment of mutations within the catalytic histone acetyltransferase (HAT) domain of CREBBP in mTORi-responders, and describe distinct transcriptional characteristics and co-occurring mutations of FL harbouring these mutations; reinforcing the growing appreciation of CREBBPHAT mutation as a key biological determinant and its promise as a therapeutic biomarker in FL.

KDM5 inhibition offers a novel therapeutic strategy for the treatment of KMT2D mutant lymphomas.

Loss-of-function mutations in KMT2D are a striking feature of germinal center (GC) lymphomas, resulting in decreased histone 3 lysine 4 (H3K4) methylation and altered gene expression. We hypothesized that inhibition of the KDM5 family, which demethylates H3K4me3/me2, would reestablish H3K4 methylation and restore the expression of genes repressed on loss of KMT2D. KDM5 inhibition increased H3K4me3 levels and caused an antiproliferative response in vitro, which was markedly greater in both endogenous and gene-edited KMT2D mutant diffuse large B-cell lymphoma cell lines, whereas tumor growth was inhibited in KMT2D mutant xenografts in vivo. KDM5 inhibition reactivated both KMT2D-dependent and -independent genes, resulting in diminished B-cell signaling and altered expression of B-cell lymphoma 2 (BCL2) family members, including BCL2 itself. KDM5 inhibition may offer an effective therapeutic strategy for ameliorating KMT2D loss-of-function mutations in GC lymphomas.

Pathogenesis of follicular lymphoma: genetics to the microenvironment to clinical translation.

Follicular lymphoma (FL) represents a heterogeneous disease both clinically and biologically. The pathognomonic t(14;18) translocation can no longer be thought of as the primary genetic driver, with increasing recognition of the biological relevance of recurrent genetic alterations in epigenetic regulators that now feature as a pivotal hallmark of this lymphoma subtype. Furthermore, sequencing studies have provided a near complete catalogue of additional genetic aberrations. Longitudinal and spatial genetic studies add an additional layer to the biological heterogeneity, providing preliminary molecular insights into high-risk phenotypes such as early progressors and transformation, and also supporting evidence for the existence of persisting re-populating cells that act as lymphoma reservoirs and harbingers for FL recurrence. Simultaneously, understanding of the tumour microenvironmental cues promoting lymphomagenesis and disease progression continue to broaden. More recently, studies are beginning to unravel the convergence and co-operation between the genetics, epigenetics and microenvironment. There is a pressing need to marry biology with therapeutics, especially with the burgeoning treatment landscape in FL, to aid in optimising patient selection and guiding the 'right drug to the right patient'.

Clinical outcomes and risk factors for severe COVID-19 in patients with haematological disorders receiving chemo- or immunotherapy.

Haematology patients receiving chemo- or immunotherapy are considered to be at greater risk of COVID-19-related morbidity and mortality. We aimed to identify risk factors for COVID-19 severity and assess outcomes in patients where COVID-19 complicated the treatment of their haematological disorder. A retrospective cohort study was conducted in 55 patients with haematological disorders and COVID-19, including 52 with malignancy, two with bone marrow failure and one immune-mediated thrombotic thrombocytopenic purpura (TTP). COVID-19 diagnosis coincided with a new diagnosis of a haematological malignancy in four patients. Among patients, 82% were on systemic anti-cancer therapy (SACT) at the time of COVID-19 diagnosis. Of hospitalised patients, 37% (19/51) died while all four outpatients recovered. Risk factors for severe disease or mortality were similar to those in other published cohorts. Raised C-reactive protein at diagnosis predicted an aggressive clinical course. The majority of patients recovered from COVID-19, despite receiving recent SACT. This suggests that SACT, where urgent, should be administered despite intercurrent COVID-19 infection, which should be managed according to standard pathways. Delay or modification of therapy should be considered on an individual basis. Long-term follow-up studies in larger patient cohorts are required to assess the efficacy of treatment strategies employed during the pandemic.

Precision medicine and lymphoma.

PURPOSE OF REVIEW: The treatment of the germinal center lymphomas, diffuse large B cell (DLBCL) and follicular lymphoma, has changed little beyond the introduction of immunochemotherapies. However, there exists a substantial group of patients within both diseases for which improvements in care will involve appropriate tailoring of treatment. RECENT FINDINGS: DLBCL consists of two major subtypes with striking differences in their clinical outcomes paralleling their underlying genetic heterogeneity. Recent studies have seen advances in the stratification of germinal center lymphomas, through comprehensive profiling of 1001 DLBCLs alongside refinements in the identification of high-risk follicular lymphoma patients using m7-FLIPI and 23G models. A new wave of novel therapeutic agents is now undergoing clinical trials for germinal center lymphomas, with BCR and EZH2 inhibitors demonstrating preferential benefit in subgroups of patients. The emergence of cell-free DNA has raised the possibility of dynamic disease monitoring to potentially mitigate the complexity of spatial and temporal heterogeneity, whilst predicting tumor evolution in real time. SUMMARY: Altogether knowledge of the genomic landscape of germinal center lymphomas is offering welcome opportunities in patient risk stratification and therapeutics. The challenge ahead is to establish how best to combine upfront or dynamic prognostication with precision therapies, while retaining practicality in clinical trials and the real-world setting.

Clinical characteristics and outcomes of HIV-associated immune complex kidney disease.

BACKGROUND: The pathogenesis and natural history of HIV-associated immune complex kidney disease (HIVICK) is not well understood. Key questions remain unanswered, including the role of HIV infection and replication in disease development and the efficacy of antiretroviral therapy (ART) in the prevention and treatment of disease. METHODS: In this multicentre study, we describe the renal pathology of HIVICK and compare the clinical characteristics of patients with HIVICK with those with IgA nephropathy and HIV-associated nephropathy (HIVAN). Poisson regression models were used to identify risk factors for each of these pathologies. RESULTS: Between 1998 and 2012, 65 patients were diagnosed with HIVICK, 27 with IgA nephropathy and 70 with HIVAN. Black ethnicity and HIV RNA were associated with HIVICK, receipt of ART with IgA nephropathy and black ethnicity and CD4 cell count with HIVAN. HIVICK was associated with lower rates of progression to end-stage kidney disease compared with HIVAN and IgA nephropathy (P < 0.0001). Patients with HIVICK who initiated ART and achieved suppression of HIV RNA experienced improvements in estimated glomerular filtration rate and proteinuria. CONCLUSIONS: These findings suggest a pathogenic role for HIV replication in the development of HIVICK and that ART may improve kidney function in patients who have detectable HIV RNA at the time of HIVICK diagnosis. Our data also suggest that IgA nephropathy should be viewed as a separate entity and not included in the HIVICK spectrum.

Longitudinal expression profiling identifies a poor risk subset of patients with ABC-type diffuse large B-cell lymphoma.

Despite the effectiveness of immuno-chemotherapy, 40% of patients with diffuse large B-cell lymphoma (DLBCL) experience relapse or refractory disease. Longitudinal studies have previously focused on the mutational landscape of relapse but fell short of providing a consistent relapse-specific genetic signature. In our study, we have focused attention on the changes in GEP accompanying DLBCL relapse using archival paired diagnostic/relapse specimens from 38 de novo patients with DLBCL. COO remained stable from diagnosis to relapse in 80% of patients, with only a single patient showing COO switching from activated B-cell-like (ABC) to germinal center B-cell-like (GCB). Analysis of the transcriptomic changes that occur following relapse suggest ABC and GCB relapses are mediated via different mechanisms. We developed a 30-gene discriminator for ABC-DLBCLs derived from relapse-associated genes that defined clinically distinct high- and low-risk subgroups in ABC-DLBCLs at diagnosis in datasets comprising both population-based and clinical trial cohorts. This signature also identified a population of <60-year-old patients with superior PFS and OS treated with ibrutinib-R-CHOP as part of the PHOENIX trial. Altogether this new signature adds to the existing toolkit of putative genetic predictors now available in DLBCL that can be readily assessed as part of prospective clinical trials.

Use of real-time ultrasound guidance for the placement of hemodialysis catheters: a systematic review and meta-analysis of randomized controlled trials.

BACKGROUND: Insertion of percutaneous hemodialysis catheters is an invasive procedure with a small but definite risk of morbidity and mortality. OBJECTIVES: Assessing potential benefits of using real-time 2-dimensional Doppler ultrasound imaging guidance for the insertion of hemodialysis catheters compared with insertion based solely on anatomic landmarks. STUDY DESIGN: Systematic review and meta-analysis of randomized controlled trials. DATA SOURCES: MEDLINE (1966 to July 2010), EMBASE (1980 to July 2010), Cochrane Renal Group Specialised Register, and Cochrane Central Register of Controlled Trials (CENTRAL). SETTING & POPULATION: Patients requiring hemodialysis catheter insertion. SELECTION CRITERIA FOR STUDIES: We included all randomized controlled trials regardless of publication status or language. INTERVENTIONS: Real-time 2-dimensional Doppler ultrasound image guidance. OUTCOMES: Catheter placement failures, catheters failed to be placed in the first attempt, attempts per catheter inserted, time taken for successful venous puncture, and complications (carotid artery puncture, pneumo- or hemothorax, neck hematoma, and brachial plexus injury). Treatment effects were summarized with the RR measure for dichotomous outcomes and mean difference for continuous outcomes. RESULTS: 7 trials with 830 catheters were identified. Ultrasound guidance significantly decreased the risk of the following outcomes: catheter placement failure (7 studies, 830 catheters; RR, 0.12; 95% CI, 0.04-0.37), failure to place catheter on first attempt (5 studies, 595 catheters; RR, 0.40; 95% CI, 0.29-0.56), arterial punctures (6 trials, 785 catheters; RR, 0.22; 95% CI, 0.06-0.81), and hematoma formation (4 trials, 323 catheters; RR, 0.27; 95% CI, 0.08-0.88). It also significantly decreased the time to cannulate the vein (1 trial, 73 catheters; mean difference, -1.40; 95% CI, -2.17 to -0.63), and number of attempts per catheter insertion (1 trial, 110 catheters; mean difference, -0.35; 95% CI, -0.54 to -0.16). LIMITATIONS: Only 7 studies were identified, of which 3 were reported in only a conference abstract form. Some outcomes were reported in only 1 study. CONCLUSIONS: Use of real-time Doppler ultrasound guidance has benefits with respect to several important clinical outcomes, and its routine use in the insertion of hemodialysis catheters is strongly recommended.

Ultrasound use for the placement of haemodialysis catheters.

BACKGROUND: A significant proportion of patients starting dialysis do so with a temporary or tunnelled haemodialysis catheter. Insertion of these catheters can be achieved either by using the anatomical landmarks for the veins into which they are inserted or using ultrasound guidance. It has been suggested that the use of ultrasound guidance reduces the immediate complications of haemodialysis catheter insertions such as pneumothorax or arterial puncture. OBJECTIVES: The aim of the review was to compare the use of real-time 2-dimensional (2-D) Doppler ultrasound venous imaging in the insertion of percutaneous central venous catheters for dialysis versus the traditional "blind" landmark method. SEARCH METHODS: We searched the Cochrane Renal Group's Specialised Register, MEDLINE, EMBASE, Cochrane Central Register of Controlled Trials (CENTRAL). Reference lists of identified studies and relevant narrative reviews were also screened. Search date: January 2011. SELECTION CRITERIA: All randomised controlled trials (RCTs) and quasi-RCTs evaluating ultrasound guidance in the percutaneous insertion of central venous catheters for dialysis (both cuffed and uncuffed) against the traditional blind landmark method. DATA COLLECTION AND ANALYSIS: Two authors assessed risk of bias and extracted data. Statistical analyses were performed using the random effects model and the results expressed as risk ratios (RR) for dichotomous outcomes or mean difference (MD) for continuous data with 95% confidence intervals (CI). MAIN RESULTS: We identified seven studies enrolling 767 patients and with 830 catheter insertions. Three of seven studies described the method of random sequence generation, none described allocation concealment, and blinding of participants and personnel was not possible. Real-time ultrasound guidance was found to significantly reduce the risk of catheter placement failure on the first attempt (5 studies, 595 catheters): RR 0.40, 95% CI 0.30 to 0.52), significantly reduce the risk of arterial puncture (6 studies, 535 catheters: RR 0.13, 95% CI 0.04 to 0.37) and haematomas (4 studies, 323 catheters: RR 0.22, 95% CI 0.06 to 0.81) when compared to the landmark method. The time taken for successful cannulation was significantly lower with the use of real-time ultrasound guidance (1 study, 73 catheters: MD -1.40 min, 95% CI -2.17 to -0.63) and there were less attempts/catheter insertion (1 study, 110 catheters: -0.35, 95% CI -0.54 to -0.16). AUTHORS' CONCLUSIONS: Use of real-time 2-D Doppler ultrasound guidance has significant benefits with respect to the number if catheters successfully inserted on the first attempt, reduction in the risk of arterial puncture and haematomas and the time taken for successful vein puncture.

The Biological Basis of Histologic Transformation.

Histologic transformation of follicular lymphoma remains the leading cause of follicular lymphoma-related mortality in the rituximab era. Both the diverse timing of transformation and heterogeneity in associated genomic events suggest that histologic transformation may itself comprise distinct disease entities. Successive indolent and transformation episodes occur by divergent clonal evolution from an inferred common progenitor cell, representing a potential therapeutic target. Existing biological knowledge largely pre-dates anti-CD20 therapy, and further prospective validation is essential. Inclusion of transformation cases in clinical trials incorporating biomarker discovery, and an integrated understanding of the genetic and microenvironmental factors underpinning transformation, may unearth renewed clinical opportunities.

Applications and analysis of targeted genomic sequencing in cancer studies.

Next Generation Sequencing (NGS) has dramatically improved the flexibility and outcomes of cancer research and clinical trials, providing highly sensitive and accurate high-throughput platforms for large-scale genomic testing. In contrast to whole-genome (WGS) or whole-exome sequencing (WES), targeted genomic sequencing (TS) focuses on a panel of genes or targets known to have strong associations with pathogenesis of disease and/or clinical relevance, offering greater sequencing depth with reduced costs and data burden. This allows targeted sequencing to identify low frequency variants in targeted regions with high confidence, thus suitable for profiling low-quality and fragmented clinical DNA samples. As a result, TS has been widely used in clinical research and trials for patient stratification and the development of targeted therapeutics. However, its transition to routine clinical use has been slow. Many technical and analytical obstacles still remain and need to be discussed and addressed before large-scale and cross-centre implementation. Gold-standard and state-of-the-art procedures and pipelines are urgently needed to accelerate this transition. In this review we first present how TS is conducted in cancer research, including various target enrichment platforms, the construction of target panels, and selected research and clinical studies utilising TS to profile clinical samples. We then present a generalised analytical workflow for TS data discussing important parameters and filters in detail, aiming to provide the best practices of TS usage and analyses.

Renal tubular disease in the era of combination antiretroviral therapy.

OBJECTIVES: To describe the spectrum of renal tubular disease (RTD) in HIV-positive patients and its association with exposure to antiretroviral therapy (ART). DESIGN: Review of 265 consecutive renal biopsies from HIV-positive patients attending eight clinics in the United Kingdom between 2000 and 2012. METHODS: We described the clinical characteristics of patients with RTD and compared current/recent exposure (at the time of, or up to 3 months prior to the date of biopsy) to potentially nephrotoxic ART [tenofovir (TDF), atazanavir (ATV), indinavir (IDV) and lopinavir/ritonavir (LPV/r)]. We also analysed the incidence of RTD in the UK CHIC cohort. Kruskall-Wallis, analysis of variance and Fisher's exact tests were used to evaluate between-group differences. RESULTS: Of the 60 RTD cases, 54 (90%) were included in the analyses. RTD comprised of three distinct patterns: acute tubular injury (ATI, n = 22), tubulo-interstitial nephritis (TIN, n = 20) and interstitial fibrosis and tubular atrophy (IFTA, n = 12). Compared with TIN and IFTA, ATI cases were less likely to be of black ethnicity (10 vs. 42-55%; P = 0.006), more likely to be on ART (100 vs. 55-68%; P = 0.001), with HIV-RNA below 200 copies/ml (100 vs. 54-58%; P < 0.001), and more likely to have current/recent exposure to TDF (P < 0.001). We did not find evidence for an association between exposure to TDF, ATV/r or LPV/r and either TIN or IFTA. CONCLUSION: RTD was present in approximately 20% of renal biopsies and comprised three distinct injury patterns with considerable clinical overlap. ATI was associated with TDF exposure, although the overall incidence of biopsy-defined ATI was low.