Response to Bruton's tyrosine kinase inhibitors in aggressive lymphomas linked to chronic selective autophagy.

Diffuse large B cell lymphoma (DLBCL) is an aggressive, profoundly heterogeneous cancer, presenting a challenge for precision medicine. Bruton's tyrosine kinase (BTK) inhibitors block B cell receptor (BCR) signaling and are particularly effective in certain molecular subtypes of DLBCL that rely on chronic active BCR signaling to promote oncogenic NF-κB. The MCD genetic subtype, which often acquires mutations in the BCR subunit, CD79B, and in the innate immune adapter, MYD88L265P, typically resists chemotherapy but responds exceptionally to BTK inhibitors. However, the underlying mechanisms of response to BTK inhibitors are poorly understood. Herein, we find a non-canonical form of chronic selective autophagy in MCD DLBCL that targets ubiquitinated MYD88L265P for degradation in a TBK1-dependent manner. MCD tumors acquire genetic and epigenetic alterations that attenuate this autophagic tumor suppressive pathway. In contrast, BTK inhibitors promote autophagic degradation of MYD88L265P, thus explaining their exceptional clinical benefit in MCD DLBCL.

Budget Impact Analysis of Minimally Invasive versus Open Transforaminal Lumbar Interbody Fusion for Lumbar Degenerative Disease: A European Hospital Perspective.

Purpose: When traditional therapies fail to provide relief from debilitating lower back pain, surgeries such as transforaminal lumbar interbody fusion (TLIF) may be required. This budget impact analysis (BIA) compared minimally-invasive (MI)-TLIF versus open (O)-TLIF for single-level fusion from an Italian hospital perspective. Methods: The BIA compared costs of 100 MI-TLIF and 100 O-TLIF procedures from an Italian hospital perspective over a one-year time horizon. The base case included costs for length of hospital stay (LOS), blood loss, and sterilizing surgical trays. The scenario analysis also included operating room (OR) time and complication costs. Base case inputs were from the Miller et al meta-analysis; scenario analysis inputs were from the Hammad et al meta-analysis. The device costs for MI-TLIF and O-TLIF procedures were from Italian tender prices for Viper Prime™ System and Expedium™ Spine System, respectively. Results: Base case deterministic analysis results showed cost savings of €207,370 for MI-TLIF compared with O-TLIF. MI-TLIF costs were lower for LOS (€215,277), transfusion for blood loss (€16,881), and surgical tray sterilization (€28,232), whereas device costs were lower for O-TLIF (€53,020). The probabilistic result was similar, with MI-TLIF resulting in savings of €211,026 (95% credible interval [CR]: €208,725 - €213,327). All 1000 base case probabilistic sensitivity analysis runs were cost saving. Deterministic scenario analysis results showed cost savings of €166,719 for MI-TLIF. MI-TLIF costs were lower for LOS (€190,813), transfusion for blood loss (€16,881), surgical tray sterilization (€28,232), and complications (€2076), whereas O-TLIF costs were lower for OR time (€18,263) and devices used (€53,020). Conclusion: Despite the increase incremental cost for medical device innovation and OR time, this study demonstrates the economic savings of MI-TLIF compared to O-TLIF from a European hospital perspective. The findings will be useful to policy and hospital decision makers in assessing purchasing, funding and reimbursement decisions.

Recurrence-Free Survival in Patients With Surgically Resected Non-Small Cell Lung Cancer: A Systematic Literature Review and Meta-Analysis.

BACKGROUND: Standard treatment for early-stage or locoregionally advanced non-small cell lung cancer (NSCLC) includes surgical resection. Recurrence after surgery is commonly reported, but a summary estimate for postsurgical recurrence-free survival (RFS) in patients with NSCLC is lacking. RESEARCH QUESTION: What is the RFS after surgery in patients with stage I-III NSCLC at different time points, and what factors are associated with RFS? STUDY DESIGN AND METHODS: A systematic search was performed in MEDLINE, EMBASE, and Cochrane databases between January 2011 and June 2021. The primary outcome was RFS at 1, 2, 3, and 5 years postresection. Single-arm, random-effects meta-analyses were done to calculate effect estimates and 95% CIs. Analyses were stratified by stage/substage as per the AJCC Cancer Staging Manual, and RFS was estimated (1) after pooling studies, using 7th or 8th edition staging criteria; and (2) among studies using only the 8th edition. Meta-regressions were performed to assess associations between RFS and patient demographic/clinical characteristics of interest. RESULTS: Data from 471 studies comprising 1,060 surgical study arms were extracted. RFS estimates from 60,695 patients staged with the 7th or 8th edition were analyzed. RFS ranged from 96% at 1 year postresection to 82% at 5 years for stage I, and from 68% at 1 year to 34% at 5 years for stage III. Estimates for patients staged using only 8th edition criteria were slightly higher. Older age, higher percentage of male patients, advancing stage, larger tumor size, and geographical region (North America/Europe vs Asia) were significantly associated with worse RFS. INTERPRETATION: This study presents a comprehensive assessment of reported RFS from published clinical literature, offering estimates at multiple postsurgical time points and by geographical region. Findings can inform treatment decisions, clinical trial design, and future research to improve outcomes among patients with NSCLC.

Emotion category-modulated interpretation bias in perceiving ambiguous facial expressions.

In contrast to prototypical facial expressions, we show less perceptual tolerance in perceiving vague expressions by demonstrating an interpretation bias, such as more frequent perception of anger or happiness when categorizing ambiguous expressions of angry and happy faces that are morphed in different proportions and displayed under high- or low-quality conditions. However, it remains unclear whether this interpretation bias is specific to emotion categories or reflects a general negativity versus positivity bias and whether the degree of this bias is affected by the valence or category of two morphed expressions. These questions were examined in two eye-tracking experiments by systematically manipulating expression ambiguity and image quality in fear- and sad-happiness faces (Experiment 1) and by directly comparing anger-, fear-, sadness-, and disgust-happiness expressions (Experiment 2). We found that increasing expression ambiguity and degrading image quality induced a general negativity versus positivity bias in expression categorization. The degree of negativity bias, the associated reaction time and face-viewing gaze allocation were further manipulated by different expression combinations. It seems that although we show a viewing condition-dependent bias in interpreting vague facial expressions that display valence-contradicting expressive cues, it appears that the perception of these ambiguous expressions is guided by a categorical process similar to that involved in perceiving prototypical expressions.

An umbrella review of the surgical performance of Harmonic ultrasonic devices and impact on patient outcomes.

BACKGROUND: For thirty years, the Harmonic scalpel has been used for precise dissection, sealing and transection. There are numerous meta-analyses on individual surgical procedures with Harmonic, but no overarching review covering all the areas. This umbrella review seeks to summarize the clinical results from the use of Harmonic across surgical fields and broadly quantify its effects on patient outcomes. METHODS: MEDLINE, EMBASE, and Cochrane Databases were searched for meta-analyses (MAs) of randomized controlled trials (RCTs) comparing Harmonic devices to conventional techniques or advanced bipolar (ABP) devices. For each procedure type, the most comprehensive MAs were evaluated. RCTs not already analysed in a MA were also included. Operating time, length of stay, intraoperative blood loss, drainage volume, pain, and overall complications were evaluated, and the methodological quality and certainty of evidence were assessed. RESULTS: Twenty-four systematic literature reviews were identified on colectomy, hemorrhoidectomy, gastrectomy, mastectomy, flap harvesting, cholecystectomy, thyroidectomy, tonsillectomy, and neck dissection. There were also 83 RCTs included. In every MA evaluated, Harmonic devices were associated with either statistically significant or numerical improvements in every outcome compared with conventional techniques; most MAs reported a reduction in operating time of ≥ 25 min. Harmonic versus ABP device MAs in colectomy and thyroidectomy showed no significant differences in outcomes. CONCLUSION: Across surgical procedures, Harmonic devices demonstrated improved patient outcomes for operating time, length of stay, intraoperative bleeding, drainage volume, pain, and overall complications compared to conventional techniques. Additional studies are required to assess differences between Harmonic and ABP devices.

Stereotactic body radiation therapy and thermal ablation for treatment of NSCLC: A systematic literature review and meta-analysis.

RATIONALE: Stereotactic body radiation therapy (SBRT) is the standard of care for inoperable early stage non-small cell lung cancer (NSCLC). Use of image guided thermal ablation (IGTA; including microwave ablation [MWA] and radiofrequency ablation [RFA]) has increased in NSCLC, however there are no studies comparing all three. OBJECTIVE: To compare the efficacy of IGTA (including MWA and RFA) and SBRT for the treatment of NSCLC. METHODS: Published literature databases were systematically searched for studies assessing MWA, RFA, or SBRT. Local tumor progression (LTP), disease-free survival (DFS), and overall survival (OS) were assessed with single-arm pooled analyses and meta-regressions in NSCLC patients and a stage IA subgroup. Study quality was assessed with a modified methodological index for non-randomized studies (MINORS) tool. RESULTS: Forty IGTA study-arms (2,691 patients) and 215 SBRT study-arms (54,789 patients) were identified. LTP was lowest after SBRT at one and two years in single-arm pooled analyses (4% and 9% vs. 11% and 18%) and at one year in meta-regressions when compared to IGTA (OR = 0.2, 95%CI = 0.07-0.63). MWA patients had the highest DFS of all treatments in single-arm pooled analyses. In meta-regressions at two and three-years, DFS was significantly lower for RFA compared to MWA (OR = 0.26, 95%CI = 0.12-0.58; OR = 0.33, 95%CI = 0.16-0.66, respectively). OS was similar across modalities, timepoints, and analyses. Older age, male patients, larger tumors, retrospective studies, and non-Asian study region were also predictors of worse clinical outcomes. In high-quality studies (MINORS score ≥ 7), MWA patients had better clinical outcomes than the overall analysis. Stage IA MWA patients had lower LTP, higher OS, and generally lower DFS, compared to the main analysis of all NSCLC patients. CONCLUSIONS: NSCLC patients had comparable outcomes after SBRT and MWA, which were better than those with RFA.

A Comparison of Microwave Ablation and Cryoablation for the Treatment of Renal Cell Carcinoma: A Systematic Literature Review and Meta-analysis.

OBJECTIVE: To conduct a systematic review and meta-analysis comparing microwave ablation (MWA) and cryoablation for renal cell carcinoma (RCC). METHODS: The systematic search was performed in MEDLINE, Embase, and Cochrane databases. Studies published in English from January 2006 to February 2022 that assessed adults with primary RCC who received MWA or cryoablation were included. Study arms from RCTs, comparative observational, and single-arm studies were eligible. The outcomes included local tumor recurrence (LTR), overall survival, disease-free survival, overall/major complications, procedure/ablation time, 1- to 3-month primary technique efficacy, and technical success. Single-arm meta-analyses were performed using the random effects model. Sensitivity analyses excluding low-quality studies assessed using the MINORs scale were performed. Univariable and multivariable examined the effects of prognostic factors. RESULTS: Baseline characteristics were similar between groups and mean tumor size for MWA and cryoablation were 2.74 and 2.69 cm. Single-arm meta-analyses were similar for LTR and secondary outcomes between cryoablation and MWA. Ablation time was significantly shorter with MWA than with cryoablation (meta-regression weighted mean difference 24.55 minutes, 95% confidence interval -31.71, -17.38, P < .0001). One-year LTR was significantly lower with MWA than cryoablation (odds ratio 0.33, 95% confidence interval 0.10-0.93, P = .04). There were no significant differences for other outcomes. CONCLUSION: MWA provides significantly improved 1-year LTR and ablation time compared with cryoablation for patients with RCC. Other outcomes appeared similar or favorable for MWA; however, results were not statistically significant. MWA of primary RCC is as safe and effective as cryoablation, which should be confirmed with future comparative studies.

Targeting N-linked Glycosylation for the Therapy of Aggressive Lymphomas.

Diffuse large B-cell lymphoma (DLBCL) can be subdivided into the activated B-cell (ABC) and germinal center B cell-like (GCB) subtypes. Self-antigen engagement of B-cell receptors (BCR) in ABC tumors induces their clustering, thereby initiating chronic active signaling and activation of NF-κB and PI3 kinase. Constitutive BCR signaling is essential in some GCB tumors but primarily activates PI3 kinase. We devised genome-wide CRISPR-Cas9 screens to identify regulators of IRF4, a direct transcriptional target of NF-κB and an indicator of proximal BCR signaling in ABC DLBCL. Unexpectedly, inactivation of N-linked protein glycosylation by the oligosaccharyltransferase-B (OST-B) complex reduced IRF4 expression. OST-B inhibition of BCR glycosylation reduced BCR clustering and internalization while promoting its association with CD22, which attenuated PI3 kinase and NF-κB activation. By directly interfering with proximal BCR signaling, OST-B inactivation killed models of ABC and GCB DLBCL, supporting the development of selective OST-B inhibitors for the treatment of these aggressive cancers. SIGNIFICANCE: DLBCL depends on constitutive BCR activation and signaling. There are currently no therapeutics that target the BCR directly and attenuate its pathologic signaling. Here, we unraveled a therapeutically exploitable, OST-B-dependent glycosylation pathway that drives BCR organization and proximal BCR signaling. This article is highlighted in the In This Issue feature, p. 1749.

Adopting a portfolio of ultrasonic and advanced bipolar electrosurgery devices from a single manufacturer compared to currently used ultrasonic and advanced bipolar devices: a probabilistic budget impact analysis from a Spanish hospital perspective.

AIMS: Advanced energy devices are commonly used in electrosurgery, including ultrasonic and advanced bipolar (ABP) devices. Smoke evacuation and reusable dispersive electrodes are also utilized during electrosurgery to improve staff and patient safety. This study assessed the budget impact of adopting a portfolio of Ethicon energy devices compared to devices from other manufacturers from a Spanish hospital perspective. METHODS: The main analysis compared the Ethicon advanced energy device portfolio (ultrasonic and ABP devices) to Non-Ethicon advanced energy devices. It was assumed that 4,000 procedures using one advanced energy device each were performed annually, and the cost impact of operating room time, length of stay, and transfusions were considered. A probabilistic budget impact analysis with 10,000 iterations was conducted for generalizability to other hospitals in Spain and Europe. Secondary analysis assessed whether cost savings from the Ethicon advanced energy device portfolio could offset costs of adopting smoke evacuation and reusable dispersive electrodes (Full Ethicon energy portfolio). RESULTS: In the main analysis, the annual budget impact of introducing the Ethicon advanced energy device portfolio was cost saving in 79.8% of probabilistic iterations (mean: -€945,214; 95% credible interval [CrI]: -€3,242,710; €1,285,942) with a mean budget impact per procedure of -€236 (95% CrI: -€811; €321). In the secondary analysis, adding smoke evacuation and reusable dispersive electrodes was still cost saving in 75.3% of iterations compared to Non-Ethicon advanced energy devices (mean: -€778,208; 95% CrI: -€3,075,086; €1,464,728) with a mean budget impact per procedure of -€97 (95% CrI: -€384; €183). Savings resulted from differences in operating room time, length of hospital stay, and volume of disposable electrodes. CONCLUSIONS: Adopting Ethicon advanced energy devices demonstrated economic benefits compared to non-Ethicon devices. Introducing the advanced portfolio may improve surgical care quality and the full portfolio was cost saving while improving OR safety for staff and patients.

This study created an economic model to calculate whether using modern electrical surgical tools with features to make cutting tissue and stopping bleeding faster and easier could save Spanish hospitals money. The electrical surgery tools from one manufacturer were compared to those from various other companies. Differences in how long surgery took to perform, how long patients stayed in hospital after their surgery, and how many blood transfusions they needed were considered in the model. The model was tested 10,000 times with random changes in the costs and settings used to be surer about the range of possible results. The results showed the devices from one manufacturer could save a Spanish hospital money in almost 80% of model runs and that savings worked out to €236 per surgery. In another analysis, savings were enough to cover the cost of introducing safety devices to remove surgical smoke from the operating room and reusable patient grounding electrodes that prevent some injuries potentially caused by small sticky electrodes. In conclusion, the model showed that Spanish hospitals may be able to save money by switching to the modern electrical surgery tools from Ethicon.

Economic analysis of n-butyl cyanoacrylate compared with ethylene vinyl alcohol copolymer liquid embolic embolization of brain arteriovenous malformations (bAVMs) from a US hospital perspective.

BACKGROUND: In US hospitals, the liquid embolic systems (LESs) n-butyl cyanoacrylate (n-BCA) and ethylene vinyl alcohol copolymer (EVOH) are used for brain arteriovenous malformation (bAVM) embolization to achieve presurgical devascularization. The aim of this study was to perform an economic analysis comparing four techniques for bAVM embolization based on LES, ancillary device, and angiography suite time costs. METHODS: An economic model was developed comparing the embolization costs for n-BCA, EVOH with the plug and push technique, EVOH with detachable-tip microcatheters, and EVOH with balloon microcatheters. Per procedure costs were calculated for bAVMs with one to four pedicles. Annual cohort analyses were performed to evaluate the potential impact for low and high-volume centers. Sensitivity analyses were performed to determine cost drivers. RESULTS: The analyses showed that the n-BCA technique was the least costly of the four techniques. Total per procedure costs for one to four embolized pedicles ranged from $5941 to $10,074 for the n-BCA technique, $8428 to $30,345 for the EVOH balloon microcatheter technique, $12,711 to $47,477 for the EVOH plug and push technique, and $13,900 to $52,233 for the EVOH detachable-tip microcatheter technique. Cohort analyses costs for 52 annual cases ranged from $308,953 to $523,838 with the n-BCA technique and from $722,816 to $2,716,096 with the EVOH detachable-tip microcatheter technique. CONCLUSIONS: Procedure costs associated with n-BCA are lower than those with each of the three EVOH techniques examined. Future cost analyses should compare the costs of new LES products once available.

Increased copy number of imprinted genes in the chromosomal region 20q11-q13.32 is associated with resistance to antitumor agents in cancer cell lines.

BACKGROUND: Parent of origin-specific allelic expression of imprinted genes is epigenetically controlled. In cancer, imprinted genes undergo both genomic and epigenomic alterations, including frequent copy number changes. We investigated whether copy number loss or gain of imprinted genes in cancer cell lines is associated with response to chemotherapy treatment. RESULTS: We analyzed 198 human imprinted genes including protein-coding genes and noncoding RNA genes using data from tumor cell lines from the Cancer Cell Line Encyclopedia and Genomics of Drug Sensitivity in Cancer datasets. We examined whether copy number of the imprinted genes in 35 different genome locations was associated with response to cancer drug treatment. We also analyzed associations of pretreatment expression and DNA methylation of imprinted genes with drug response. Higher copy number of BLCAP, GNAS, NNAT, GNAS-AS1, HM13, MIR296, MIR298, and PSIMCT-1 in the chromosomal region 20q11-q13.32 was associated with resistance to multiple antitumor agents. Increased expression of BLCAP and HM13 was also associated with drug resistance, whereas higher methylation of gene regions of BLCAP, NNAT, SGK2, and GNAS was associated with drug sensitivity. While expression and methylation of imprinted genes in several other chromosomal regions was also associated with drug response and many imprinted genes in different chromosomal locations showed a considerable copy number variation, only imprinted genes at 20q11-q13.32 had a consistent association of their copy number with drug response. Copy number values among the imprinted genes in the 20q11-q13.32 region were strongly correlated. They were also correlated with the copy number of cancer-related non-imprinted genes MYBL2, AURKA, and ZNF217 in that chromosomal region. Expression of genes at 20q11-q13.32 was associated with ex vivo drug response in primary tumor samples from the Beat AML 1.0 acute myeloid leukemia patient cohort. Association of the increased copy number of the 20q11-q13.32 region with drug resistance may be complex and could involve multiple genes. CONCLUSIONS: Copy number of imprinted and non-imprinted genes in the chromosomal region 20q11-q13.32 was associated with cancer drug resistance. The genes in this chromosomal region may have a modulating effect on tumor response to chemotherapy.

Hemodialysis Arteriovenous Access Cosmesis Scale (AVACS): A new measure for vascular access.

RATIONALE AND OBJECTIVE: This study aimed to develop a cosmesis scale to evaluate the cosmetic appearance of hemodialysis (HD) arteriovenous (AV) accesses from the perspective of the patient and clinician, which could be incorporated into clinical trials. STUDY DESIGN: Using a modified Delphi process, two AV access cosmesis scale (AVACS) components were developed in a four-round Delphi panel consisting of two surveys and two consensus meetings with two rounds of patient consultation. SETTING AND PARTICIPANTS: The Delphi panel consisted of 15 voting members including five interventional or general nephrologists, five vascular surgeons, three interventional radiologists, and two vascular access nurse coordinators. Four patients experienced with vascular access were involved in patient question development. ANALYTICAL APPROACH: For a component to be included in the AVACS, it had to meet the prespecified panel consensus agreement of ⩾70%. RESULTS: The clinician component of the AVACS includes nine questions on the following AV access features: scarring, skin discoloration, aneurysm/pseudoaneurysms and megafistula appearance. The patient component includes six questions about future vascular access decisions, interference with work or leisure activities, clothing choices, self-consciousness or attractiveness, emotional impact, and overall appearance. LIMITATIONS: Delphi panel methods are subjective by design, but with expert clinical opinion are used to develop classification systems and outcome measures. The developed scale requires further validation testing but is available for clinical trial use. CONCLUSIONS: While safety and efficacy are the primary concerns when evaluating AV access for HD, cosmesis is an important component of the ESKD patient experience. The AVACS has been designed to assess this important domain; it can be used to facilitate patient care and education about vascular access choice and maintenance. AVACS can also be used to inform future research on developing new techniques for AV access creation and maintenance, particularly as relates to AV access cosmesis.

Oncogenic RAS commandeers amino acid sensing machinery to aberrantly activate mTORC1 in multiple myeloma.

Oncogenic RAS mutations are common in multiple myeloma (MM), an incurable malignancy of plasma cells. However, the mechanisms of pathogenic RAS signaling in this disease remain enigmatic and difficult to inhibit therapeutically. We employ an unbiased proteogenomic approach to dissect RAS signaling in MM. We discover that mutant isoforms of RAS organize a signaling complex with the amino acid transporter, SLC3A2, and MTOR on endolysosomes, which directly activates mTORC1 by co-opting amino acid sensing pathways. MM tumors with high expression of mTORC1-dependent genes are more aggressive and enriched in RAS mutations, and we detect interactions between RAS and MTOR in MM patient tumors harboring mutant RAS isoforms. Inhibition of RAS-dependent mTORC1 activity synergizes with MEK and ERK inhibitors to quench pathogenic RAS signaling in MM cells. This study redefines the RAS pathway in MM and provides a mechanistic and rational basis to target this mode of RAS signaling.

The value of mass-produced COVID-19 scenarios: A quality evaluation of development processes and scenario content.

Hundreds of scenarios were developed across the world in 2020, aimed at generating forward-looking conversations, better understanding for COVID-19 transmission rates, trialling economic outcomes, and stress-testing existing systems in light of the developing pandemic. In response, Cairns & Wright (2020) questioned the value of these mass-produced scenarios created retroactively to existing crises. We address their concerns by evaluating 213 COVID-19 scenarios developed in the first wave of the pandemic. We use two yardsticks as guiding maps against which we plot each scenario's profile and test for values of high-quality process and content. Our analyses reveal various points of high and low qualities, in both process and content. Though most reported processes fell towards lower quality standards, and content largely carried generic applications, the prolific levels of exploratory narratives reflected a mixture of high and low-quality values. Together, our papers develop and reinforce the message that scenario interventions, especially in times of crisis, should reflect more proactive efforts and ensure powerful stakeholders, decision-makers, and affected community members are included in the development of scenarios.

Gene Expression Signatures for the Accurate Diagnosis of Peripheral T-Cell Lymphoma Entities in the Routine Clinical Practice.

PURPOSE: Peripheral T-cell lymphoma (PTCL) includes heterogeneous clinicopathologic entities with numerous diagnostic and treatment challenges. We previously defined robust transcriptomic signatures that distinguish common PTCL entities and identified two novel biologic and prognostic PTCL-not otherwise specified subtypes (PTCL-TBX21 and PTCL-GATA3). We aimed to consolidate a gene expression-based subclassification using formalin-fixed, paraffin-embedded (FFPE) tissues to improve the accuracy and precision in PTCL diagnosis. MATERIALS AND METHODS: We assembled a well-characterized PTCL training cohort (n = 105) with gene expression profiling data to derive a diagnostic signature using fresh-frozen tissue on the HG-U133plus2.0 platform (Affymetrix, Inc, Santa Clara, CA) subsequently validated using matched FFPE tissues in a digital gene expression profiling platform (nCounter, NanoString Technologies, Inc, Seattle, WA). Statistical filtering approaches were applied to refine the transcriptomic signatures and then validated in another PTCL cohort (n = 140) with rigorous pathology review and ancillary assays. RESULTS: In the training cohort, the refined transcriptomic classifier in FFPE tissues showed high sensitivity (> 80%), specificity (> 95%), and accuracy (> 94%) for PTCL subclassification compared with the fresh-frozen-derived diagnostic model and showed high reproducibility between three independent laboratories. In the validation cohort, the transcriptional classifier matched the pathology diagnosis rendered by three expert hematopathologists in 85% (n = 119) of the cases, showed borderline association with the molecular signatures in 6% (n = 8), and disagreed in 8% (n = 11). The classifier improved the pathology diagnosis in two cases, validated by clinical findings. Of the 11 cases with disagreements, four had a molecular classification that may provide an improvement over pathology diagnosis on the basis of overall transcriptomic and morphological features. The molecular subclassification provided a comprehensive molecular characterization of PTCL subtypes, including viral etiologic factors and translocation partners. CONCLUSION: We developed a novel transcriptomic approach for PTCL subclassification that facilitates translation into clinical practice with higher precision and uniformity than conventional pathology diagnosis.

Effect of ibrutinib with R-CHOP chemotherapy in genetic subtypes of DLBCL.

In diffuse large B cell lymphoma (DLBCL), tumors belonging to the ABC but not GCB gene expression subgroup rely upon chronic active B cell receptor signaling for viability, a dependency that is targetable by ibrutinib. A phase III trial ("Phoenix;" ClinicalTrials.gov: NCT01855750) showed a survival benefit of ibrutinib addition to R-CHOP chemotherapy in younger patients with non-GCB DLBCL, but the molecular basis for this benefit was unclear. Analysis of biopsies from Phoenix trial patients revealed three previously characterized genetic subtypes of DLBCL: MCD, BN2, and N1. The 3-year event-free survival of younger patients (age ≤60 years) treated with ibrutinib plus R-CHOP was 100% in the MCD and N1 subtypes while the survival of patients with these subtypes treated with R-CHOP alone was significantly inferior (42.9% and 50%, respectively). This work provides a mechanistic understanding of the benefit of ibrutinib addition to chemotherapy, supporting its use in younger patients with non-GCB DLBCL.

Overcoming Acquired Epigenetic Resistance to BTK Inhibitors.

The use of Bruton tyrosine kinase (BTK) inhibitors to block B-cell receptor (BCR)-dependent NF-κB activation in lymphoid malignancies has been a major clinical advance, yet acquired therapeutic resistance is a recurring problem. We modeled the development of resistance to the BTK inhibitor ibrutinib in the activated B-cell (ABC) subtype of diffuse large B-cell lymphoma, which relies on chronic active BCR signaling for survival. The primary mode of resistance was epigenetic, driven in part by the transcription factor TCF4. The resultant phenotypic shift altered BCR signaling such that the GTPase RAC2 substituted for BTK in the activation of phospholipase Cγ2, thereby sustaining NF-κB activity. The interaction of RAC2 with phospholipase Cγ2 was also increased in chronic lymphocytic leukemia cells from patients with persistent or progressive disease on BTK inhibitor treatment. We identified clinically available drugs that can treat epigenetic ibrutinib resistance, suggesting combination therapeutic strategies. SIGNIFICANCE: In diffuse large B-cell lymphoma, we show that primary resistance to BTK inhibitors is due to epigenetic rather than genetic changes that circumvent the BTK blockade. We also observed this resistance mechanism in chronic lymphocytic leukemia, suggesting that epigenetic alterations may contribute more to BTK inhibitor resistance than currently thought.See related commentary by Pasqualucci, p. 555. This article is highlighted in the In This Issue feature, p. 549.

Multilayer Watertight Closure to Address Adverse Events From Primary Total Knee and Hip Arthroplasty: A Systematic Review of Wound Closure Methods by Tissue Layer.

BACKGROUND: Wound closure is a key, and often underrecognized, component of hip and knee arthroplasty. Methods for wound closure are an important consideration to better avoid wound-related adverse events; however, there is a lack of consensus on optimal methods. The objective of the following review was twofold: to characterize the wound closure methods used by layer in the total knee arthroplasty and total hip arthroplasty literature and summarize optimal wound-healing strategies to address the risk of adverse events. METHODS: A systematic literature review was performed to identify total knee arthroplasty and total hip arthroplasty randomized controlled trials and nonrandomized studies reporting wound closure methods by layer and wound-healing adverse events (including superficial, deep, or periprosthetic joint infections, wound dehiscence, or prolonged wound drainage). Studies on revision procedures were excluded. Wound closure methods and adverse events were summarized qualitatively as meta-analyses were not possible because of study heterogeneity. RESULTS: Forty studies met the inclusion criteria: 22 randomized controlled trials and 18 observational studies. Across studies, 6 categories and 22 unique techniques for closure were identified. Conventional closure methods exhibited large ranges of adverse event rates. Studies of multilayer barbed sutures with topical skin adhesives and polyester mesh or multilayer antimicrobial sutures reported narrow ranges of adverse events rates. CONCLUSIONS: Considerable variability exists for wound closure methods, with a wide range reported in adverse events. Recent technologies and methods for standardized watertight, multilayer closure show promise for avoiding adverse events and unnecessary health-care costs; however, higher quality, comparative studies are required to enable future meta-analyses. LEVEL OF EVIDENCE: Therapeutic Level IV. See Instructions for Authors for a complete description of levels of evidence.