A narrative review of gas separation and conservation technologies during xenon anesthesia.

Xenon gas has significant advantages over conventional general anesthetic agents but its use has been limited by the cost associated with its production. Xenon also has significant potential for medical use in the treatment of acquired brain injuries and for mental health disorders. As the demand for xenon gas from other industries increases, the costs associated with its medical use are only likely to increase. One solution to mitigate the significant cost of xenon use in research or medical care is the conservation of xenon gas. During delivery of xenon anesthesia, this can be achieved either by separating xenon from the other gases within the anesthetic circuit, conserving xenon and allowing other gases to be excluded from the circuit, or by selectively recapturing xenon utilized during the anesthetic episode at the conclusion of the case. Several technologies, including the pressurization and cooling of gas mixtures, the utilization of gas selective membranes and the utilization of gas selective adsorbents have been described in the literature for this purpose. These techniques are described in this narrative review along with important clinical context that informs how these technologies might be best applied. Whilst these technologies are discussed in the context of xenon general anesthesia, they could be applied in the delivery of xenon gas inhalation for other therapeutic purposes.

CNS Relapse in High-Grade B-cell Lymphoma with MYC and BCL2 Rearrangements and Dark-Zone Signature-Expressing DLBCL.

High-grade B-cell lymphoma with MYC and BCL2 rearrangements (HGBCL-DH-BCL2), or 'double-hit lymphoma,' has been associated with a high risk of central nervous system (CNS) relapse. However, historic estimates are impacted by selection bias. We report CNS relapse rates associated with HGBCL-DH-BCL2 from a population-based cohort with complete fluorescence in situ hybridization testing, as well as diffuse large B-cell lymphoma morphology (DLBCL) tumors expressing the dark-zone gene expression signature (DZsig), which was originally derived from HGBCL-DH-BCL2. The 2-year CNS relapse risk in HGBCL-DH-BCL2 was 6.8%. CNS relapses were early, predominantly leptomeningeal (73%) and co-occurred with systemic relapse (64%). High-risk CNS International Prognostic Index (CNS-IPI) and concordant bone marrow involvement were associated with an elevated CNS relapse risk in HGBCL-DH-BCL2. The 'refined cell of origin' classification assigned 20% of DLBCL morphology tumors with germinal center B-cell-like phenotype (GCB-DLBCL) into a distinct subgroup based on DZsig expression (DZsig+). CNS relapse risk in DZsig+ (2-year: 6.4%) was independent of HGBCL-DH-BCL2 status and was further stratified by the CNS-IPI. CNS relapse in DZsig-negative GCB-DLBCL was rare (2-year risk 1.4%; P=.04 versus DZsig+) and exclusively parenchymal. Altogether, the CNS relapse risk in HGBCL-DH-BCL2 is lower than previously reported and DZsig refines risk stratification in GCB-DLBCL.

Sarcopenia in general practice: Towards improving muscle health screening, assessment and management in Australia.

BACKGROUND: An estimated one in five Australians aged 60 years and older have sarcopenia, marked by progressive and accelerated loss in muscle mass, strength and function. Sarcopenia is associated with considerable healthcare costs and a myriad of adverse health outcomes, including increased risk of death. Despite its clinical importance, muscle health is often overlooked in routine clinical practice, hindering diagnosis and treatment. OBJECTIVE: In July 2023, eight representatives from Australia's primary care and research communities convened to discuss barriers to sarcopenia screening, assessment and management within routine clinical practice. Solutions were proposed to improve the implementation of muscle health assessment and management in general practice. This article summarises the key discussions and outcomes from this meeting. DISCUSSION: Strategies to improve the implementation of muscle health assessment and management in general practice include (1) improving public awareness; (2) professional education; (3) provision of tools and resources; (4) advocacy and policy; and (5) increasing collaborative efforts between healthcare professionals, professional societies, universities, electronic medical record software vendors and the government.

Transperineal biopsy devices in people with suspected prostate cancer - a systematic review and economic evaluation.

Background: People with suspected prostate cancer are usually offered either a local anaesthetic transrectal ultrasound-guided prostate biopsy or a general anaesthetic transperineal prostate biopsy. Transperineal prostate biopsy is often carried out under general anaesthetic due to pain caused by the procedure. However, recent studies suggest that performing local anaesthetic transperineal prostate biopsy may better identify cancer in particular regions of the prostate and reduce infection rates, while being carried out in an outpatient setting. Devices to assist with freehand methods of local anaesthetic transperineal prostate may also help practitioners performing prostate biopsies. Objectives: To evaluate the clinical effectiveness and cost-effectiveness of local anaesthetic transperineal prostate compared to local anaesthetic transrectal ultrasound-guided prostate and general anaesthetic transperineal prostate biopsy for people with suspected prostate cancer, and local anaesthetic transperineal prostate with specific freehand devices in comparison with local anaesthetic transrectal ultrasound-guided prostate and transperineal prostate biopsy conducted with a grid and stepping device conducted under local or general anaesthetic. Data sources and methods: We conducted a systematic review of studies comparing the diagnostic yield and clinical effectiveness of different methods for performing prostate biopsies. We used pairwise and network meta-analyses to pool evidence on cancer detection rates and structured narrative synthesis for other outcomes. For the economic evaluation, we reviewed published and submitted evidence and developed a model to assess the cost-effectiveness of the different biopsy methods. Results: We included 19 comparative studies (6 randomised controlled trials and 13 observational comparative studies) and 4 single-arm studies of freehand devices. There were no statistically significant differences in cancer detection rates for local anaesthetic transperineal prostate (any method) compared to local anaesthetic transrectal ultrasound-guided prostate (relative risk 1.00, 95% confidence interval 0.85 to 1.18) (n = 5 randomised controlled trials), as was the case for local anaesthetic transperineal prostate with a freehand device compared to local anaesthetic transrectal ultrasound-guided prostate (relative risk 1.40, 95% confidence interval 0.96 to 2.04) (n = 1 randomised controlled trial). Results of meta-analyses of observational studies were similar. The economic analysis indicated that local anaesthetic transperineal prostate is likely to be cost-effective compared with local anaesthetic transrectal ultrasound-guided prostate (incremental cost below £20,000 per quality-adjusted life-year gained) and less costly and no less effective than general anaesthetic transperineal prostate. local anaesthetic transperineal prostate with a freehand device is likely to be the most cost-effective strategy: incremental cost versus local anaesthetic transrectal ultrasound-guided prostate of £743 per quality-adjusted life-year for people with magnetic resonance imaging Likert score of 3 or more at first biopsy. Limitations: There is limited evidence for efficacy in detecting clinically significant prostate cancer. There is comparative evidence for the PrecisionPoint™ Transperineal Access System (BXTAccelyon Ltd, Burnham, UK) but limited or no evidence for the other freehand devices. Evidence for other outcomes is sparse. The cost-effectiveness results are sensitive to uncertainty over cancer detection rates, complication rates and the numbers of core samples taken with the different biopsy methods and the costs of processing them. Conclusions: Transperineal prostate biopsy under local anaesthetic is equally efficient at detecting prostate cancer as transrectal ultrasound-guided prostate biopsy under local anaesthetic but it may be better with a freehand device. local anaesthetic transperineal prostate is associated with urinary retention type complications, whereas local anaesthetic transrectal ultrasound-guided prostate has a higher infection rate. local anaesthetic transperineal prostate biopsy with a freehand device appears to meet conventional levels of costeffectiveness compared with local anaesthetic transrectal ultrasound-guided prostate. Study registration: This study is registered as PROSPERO CRD42021266443. Funding: This award was funded by the National Institute for Health and Care Research (NIHR) Evidence Synthesis programme (NIHR award ref: NIHR134220) and is published in full in Health Technology Assessment Vol. 28, No. 60. See the NIHR Funding and Awards website for further award information.

A prostate biopsy can help determine if a person has prostate cancer. The main ways of performing a prostate biopsy involve taking small samples of the prostate out through the rectum (back passage) or through the perineum ­ the skin area between the anus and the scrotum (testicles). Both methods use ultrasound images from a probe inserted into the rectum to help the clinician see what they are doing. Taking samples through the rectum is usually carried out under local anaesthetic, whereas taking samples through the perineum is usually carried out under general anaesthetic. We wanted to find out if taking samples through the perineum under local anaesthetic (instead of general anaesthetic) would be equally effective at detecting prostate cancer as the other biopsy methods and whether there was any improvement or change in the sorts of side effects people may have. We also wanted to know if people found the biopsy painful or not. We carried out searches of computer research databases to find relevant clinical and cost-effectiveness studies and compared the effectiveness of the different biopsy methods they used. We read and summarised the results of the studies we found in our search. Our findings showed that taking biopsy samples through the perineum under local anaesthetic had rates of detecting prostate cancer similar to those of the other biopsy methods. But if the clinician also used a freehand device that helps guide the biopsy needle as part of the procedure, then this may be a better method for detecting cancer. The studies we found agreed that performing this prostate biopsy under local anaesthetic was not too painful for most people. Our economic estimates suggest that using a freehand device for local anaesthetic perineal (through the skin of the perineum) biopsy may be a cost-effective use of National Health Service resources.

MYC-rearranged mature B-cell lymphomas in children and young adults are molecularly Burkitt Lymphoma.

Aggressive B-cell non-Hodgkin lymphomas (NHL) in children, adolescents, and young adults (CAYA) include Burkitt lymphoma (BL), diffuse large B-cell lymphoma (DLBCL), and a subset of high-grade tumors with features intermediate between these entities whose genetic and molecular profiles have not been completely elucidated. In this study, we have characterized 37 aggressive B-NHL in CAYA, 33 with high-grade morphology, and 4 DLBCL with MYC rearrangement (MYC-R), using targeted next-generation sequencing and the aggressive lymphoma gene expression germinal center B-cell-like (GCB), activated B-cell-like (ABC), and dark zone signatures (DZsig). Twenty-two tumors had MYC-R without BCL2 breaks, and two MYC-non-R cases had BCL6 translocations. MYC-R cases, including DLBCL, carried BL-related mutations and copy number alterations. Conversely, MYC-non-R lymphomas had alterations in the B-cell receptor signaling/NF-κB pathway (71%). DZsig was expressed in 12/13 of MYC-R tumors but only in 2/10 of MYC-non-R GCB tumors (P < 0.001). The 3-year event-free survival (EFS) of the whole cohort was 79.6%. TP53 and KMT2C mutations conferred inferior outcome (3-year EFS P < 0.05). Overall, MYC-R lymphomas in CAYA have a molecular profile similar to BL regardless of their high-grade or DLBCL morphology, whereas MYC-non-R has more heterogeneous genetic alterations closer to that of DLBCL.

Aberrant BCAT1 expression augments MTOR activity and accelerates disease progression in chronic lymphocytic leukemia.

We performed gene expression profiling of mRNA/cDNA isolated from N = 117 flow sorted CLL. We detected aberrant expression of the metabolic enzyme branched chain amino acid transferase (BCAT1) in CLL with del17p/TP53mut. Through extensive validation, we confirmed the highly preferential expression of BCAT1 in CLL with del17p/TP53mut (66%) or trisomy 12 (77%). BCAT1 was not expressed in B cells isolated from normal human lymph nodes. The products of the bidirectional BCAT1 reaction, including leucine, acetyl-CoA, and alpha-ketoglutarate are known activators of MTOR. We measured an ~two-fold higher MTOR activity via normalized p-S6K levels in primary CLL with BCAT1 high versus absent expression before and after sIgM crosslinking. Through steady state metabolomics and heavy isotope metabolic tracing in primary CLL cells, we demonstrate that CLL cells are avid consumers of branched chain amino acids (BCAAs) and that BCAT1 in CLL engages in bidirectional substrate reactions. Of additional interest, CLL with aberrant BCAT1 expression were less sensitive to Venetoclax-induced apoptosis. Biologically, three CLL-derived cell lines with disruption of BCAT1 had substantially reduced growth ex vivo. Clinically, the expression of any detectable BCAT1 protein in CLL independently associated with shorter median survival (125 months versus 296 months; p < 0.0001), even after exclusion of del17p/TP53mut cases.

Maximum disease diameter is associated with outcomes in stage II follicular lymphoma treated with radiation therapy alone.

Purpose: The optimal management of stage II follicular lymphoma (FL) is unclear. Radiation therapy (RT) alone has been the gold standard treatment, but a proportion of patients relapse. We sought to characterize outcomes and prognostic factors for stage II FL treated with RT alone to identify a high-risk subgroup of patients who may benefit from treatment intensification. Methods: This was a population-based, province-wide, retrospective study. Included patients had grade 1-3A, non-mesenteric, stage IIA or IIAE FL diagnosed between 1986 and 2016 and treated with curative-intent (≥20 Gy) RT alone. Results: 102 patients were included. Median follow-up was 10.4 years (range, 0.3-22.3). Median age was 59 years (range, 33-86). Median greatest disease diameter was 3.6 cm (range, 1.5-11.5). Freedom from progression (FFP) was 60.3% at 5 years and 40.7% at 10 years. Overall survival (OS) was 89.2% at 5 years and 81.8% at 10 years. Greatest disease diameter of >3.6 cm was associated with inferior FFP (10-year FFP 34% vs. 47%, p = 0.013) on univariable analysis and inferior FFP (hazard ratio [HR] 1.87, p = 0.019) and inferior OS (HR 2.12, p = 0.027) on multivariable analysis (MVA). Older age was associated with inferior OS (HR 1.08, unit = 1 year, p < 0.001) on MVA. Conclusions: 40.7% of stage II FL patients treated with RT alone remained disease-free at 10 years. Greatest disease diameter >3.6 cm was associated with inferior FFP and OS, representing a novel prognostic indicator in this population that may help in the decision-making process on whether to complement RT with systemic therapy.

Genetically encoded fluorescent sensors for visualizing polyamine levels, uptake, and distribution.

Polyamines are abundant and physiologically essential biomolecules that play a role in numerous processes, but are disrupted in diseases such as cancer, and cardiovascular and neurological disorders. Despite their importance, measuring free polyamine concentrations and monitoring their metabolism and uptake in cells in real-time remains impossible due to the lack of appropriate biosensors. Here we engineered, characterized, and validated the first genetically encoded biosensors for polyamines, named iPASnFRs. We demonstrate the utility of iPASnFR for detecting polyamine import into mammalian cells, to the cytoplasm, mitochondria, and the nucleus. We demonstrate that these sensors are useful to probe the activity of polyamine transporters and to uncover biochemical pathways underlying the distribution of polyamines amongst organelles. The sensors powered a high-throughput small molecule compound library screen, revealing multiple compounds in different chemical classes that strongly modulate cellular polyamine levels. These sensors will be powerful tools to investigate the complex interplay between polyamine uptake and metabolic pathways, address open questions about their role in health and disease, and enable screening for therapeutic polyamine modulators.

Delineation of global, absolutely essential and conditionally essential pangenomes of Porphyromonas gingivalis.

Porphyromonas gingivalis is a Gram-negative, anaerobic oral pathobiont, an etiological agent of periodontitis and the most commonly studied periodontal bacterium. Multiple low passage clinical isolates were sequenced, and their genomes compared to several laboratory strains. Phylogenetic distances were mapped, a gene absence-presence matrix generated, and core (present in all genomes) and accessory (absent in one or more genomes) genes delineated. Subsequently, a second pangenome delineating the prevalence of inherently essential genes was generated. The prevalence of genes conditionally essential for surviving tobacco exposure, abscess formation and epithelial invasion was also determined, in addition to genes encoding key proteolytic enzymes containing putative signal peptides. While the absolutely essential pangenome was highly conserved, significant differences in the complete and conditionally essential pangenomes were apparent. Thus, genetic plasticity appears to lie primarily in gene sets facilitating adaptation to variant disease-related environments. Those genes that are highly pervasive in the P. gingivalis absolutely essential pangenome or are highly prevalent and essential for fitness in disease-relevant models, may represent particularly attractive therapeutic targets worthy of further investigation. As mutations in absolutely essential genes are expected to be lethal, the data provided herein should also facilitate improved planning for P. gingivalis gene mutation strategies.

A randomized trial of ibrutinib and R-GDP prior to stem cell transplant in relapsed diffuse large B-cell lymphoma.

In the LY.17 randomized phase II clinical trial, adults with relapsed and refractory diffuse large B-cell lymphoma treated with ibrutinib-R-GDP (IR-GDP) for up to three cycles had more documented bacterial and fungal infections, without improvement in overall response, compared with R-GDP. CR, complete response; DLBCL, diffuse large B-cell lymphoma; PD, progressive disease; PR, partial response; R/R, relapsed/refractory; SD, stable disease.

Production of recombinant adeno-associated virus 5 using a novel self-attenuating adenovirus production platform.

Recombinant adeno-associated virus (rAAV) has become a prominent vector for clinical use. Despite an increase in successful clinical outcomes, the amount of high-quality rAAVs required for clinical trials and eventual commercial demand is difficult to produce, especially for genetic diseases that are prevalent or require high doses. Many groups are focused on establishing production processes that can produce sufficient rAAV while maintaining potency and quality. Our group used a novel production platform to increase our yield of rAAV5. This production platform uses tetracycline-enabled self-silencing adenovirus (TESSA) to deliver the wild-type AAV replication and capsid genes alongside the adenovirus helper genes necessary for production. Here, we describe our efforts to evaluate the TESSA platform in house. We conducted numerous experiments to determine the optimal conditions for producing rAAV5 from the TESSA production system. We then produced rAAV5 from the TESSA system to compare against rAAV5 produced from triple transfection. Ultimately, we generated data that showed that the vector genome yield of rAAV5 produced with TESSA was >20-fold higher than rAAV5 produced with triple transfection. Additionally, our data show that quality as well as potency in mice of rAAV5 produced with the TESSA system and by triple transfection are equivalent.

Identification, risk factors, and clinical course of CNS relapse in DLBCL patients across 19 prospective phase 2 and 3 trials-a LYSA and GLA/ DSHNHL collaboration.

Progression or relapse in the central nervous system (CNS) remains a rare but mostly fatal event for patients with diffuse large B-cell lymphoma (DLBCL). In a retrospective analysis of 5189 patients treated within 19 prospective German and French phase 2/3 trials, we identified 159 patients experiencing a CNS event (relapse: 62%, progression: 38%). Intracerebral, meningeal, intraspinal, or combined involvement was reported in 44%, 31%, 3%, and 22% of patients, respectively. 62 of 155 evaluable patients (40%) showed concurrent systemic progression/ relapse. 82% of all CNS events occurred within two years after study inclusion or randomization. 87% of patients showed extranodal involvement outside the CNS. Patients generally had poor outcomes with a median overall survival (OS) of 3.4 months (95% CI 2.9-4.2) and a 2-year OS of 15% (10-22%). Outcomes did not differ depending on the site or time point of CNS events. Patients with isolated CNS events demonstrated significantly better OS (p = 0.023). Twenty-five patients were consolidated with autologous or allogeneic stem cell transplantation and achieved a 3-year OS of 36% (20-66%). This large study including more than 5000 DLBCL patients highlights the unmet medical need to improve the outcome of DLBCL patients suffering from CNS relapse.

Unbalanced MYC break-apart FISH patterns indicate the presence of a MYC rearrangement in HGBCL-DH-BCL2.

ABSTRACT: Fluorescence in situ hybridization (FISH) using break-apart probes is recommended for identifying high-grade B-cell lymphoma with MYC and BCL2 rearrangements (HGBCL-DH-BCL2). Unbalanced MYC break-apart patterns, in which the red or green signal is lost, are commonly reported as an equivocal result by clinical laboratories. In a cohort of 297 HGBCL-DH-BCL2, 13% of tumors had unbalanced MYC break-apart patterns with loss of red (LR; 2%) or loss of green (LG; 11%) signal. To determine the significance of these patterns, MYC rearrangements were characterized by sequencing in 130 HGBCL-DH-BCL2, including 3 LR and 14 LG tumors. A MYC rearrangement was identified for 71% of tumors with LR or LG patterns, with the majority involving immunoglobulin loci or other recurrent MYC rearrangement partners. The architecture of these rearrangements consistently preserved the rearranged MYC allele, with the MYC gene predicted to be on the derivative chromosome containing the signal that is still present in nearly all cases. MYC protein expression, MYC messenger RNA expression, and the proportion of tumors expressing the dark-zone signature was not significantly different between balanced and unbalanced groups. These results support a recommendation that unbalanced MYC break-apart FISH patterns be reported as positive for MYC rearrangement in the context of diagnosing HGBCL-DH-BCL2.

If the peri-operative patient pathway was right, what would it look like?

BACKGROUND: Patients undergoing surgery deserve the best possible peri-operative outcomes. Each stage of the peri-operative patient journey offers opportunities to improve care delivery, with shorter lengths of stay, less complications, reduced costs and better value. METHODS: These opportunities were identified through narrative review of the literature, with consultation and consensus at the hidden pandemic (of postoperative complications) summit 2, July 2023 in Adelaide, Australia RESULTS: Before surgery: Some patients who receive timely alternative treatments may not need surgery at all. The period of waiting after listing should be a time of preparation. Risk assessment at the time of surgical listing facilitates recognition of need for comorbidity optimisation and identifies those who will most benefit from prehabilitation, particularly frail and deconditioned patients. DURING SURGERY: During the surgical admission, ERAS programs result in less postoperative complications, shorter length of stay and better patient experience but require agreement between clinicians, and coordinated monitoring of delivery of the elements in the ERAS bundle of care. AFTER SURGERY: At-risk patients need to have the appropriate levels of monitoring for cardiovascular instability, renal impairment or respiratory dysfunction, to facilitate timely, proactive management if they develop. Access to allied health in the early postoperative period is also critical for promoting mobility, and earlier discharge, particularly after joint surgery. Where appropriate, provision of rehabilitation services at home improves patient experience and adds value. The peri-operative patient journey begins and ends with primary care so there is a need for clear communication, documentation, around sharing of responsibility between practitioners at each stage. CONCLUSION: Identifying and mitigating risk to reduce complications and length of stay in hospital will improve outcomes for patients and deliver the best value for the health system.

Prevalence of neurocognitive disorders 5 years after elective orthopaedic surgery.

BACKGROUND: Peri-operative neurocognitive disorders are one of the most common complications affecting older adults after anaesthesia and surgery. It is not clear how exposure to surgery and anaesthesia contributes to the prevalence of long-term neurocognitive disorders. This study aimed to report the prevalence of neurocognitive disorders, and explore pre-operative factors associated with neurocognitive disorders 5 years after elective orthopaedic surgery. METHODS: A prospective, 5-year longitudinal, cohort study was performed recruiting patients (aged ≥ 60 y) undergoing elective orthopaedic surgery and a contemporaneous non-surgical control group. Neurocognitive disorder was evaluated and classified at baseline and 5-year review incorporating: self- and informant-reported cognition; functional participation; and performance on neuropsychological tests. RESULTS: Recruitment at 5-year follow-up included 195 patients and 21 control participants. In the patient cohort the prevalence of neurocognitive disorder was 38.1% (n = 75), with 61 (30.1%) meeting the criteria for mild neurocognitive disorder and 14 (7.1%) for major neurocognitive disorder. At 5-year follow-up, 121 (61.4%) patients were classified with a neurocognitive disorder, with 88 (44.7%) characterised with mild neurocognitive disorder and 33 (16.8%) with major neurocognitive disorder. Age (odds ratio (95%CI) 1.07 (1.02-1.13); p = 0.01) and baseline cognitive impairment (odds ratio (95%CI) 2.1 (1.06-4.15); p = 0.03) were significant predictors of neurocognitive disorder 5 years after surgery. CONCLUSION: More than half of older adult patients had some form of neurocognitive disorder 5 years after elective orthopaedic surgery. Surgery and anaesthesia may be associated with the trajectory of cognitive decline in at-risk older adults, including those with pre-operative cognitive impairment. Cognitive screening should be factored into pre-operative assessments of older adults to inform subsequent care.

From hit to vial: Precision discovery and development of an imidazopyrimidine TLR7/8 agonist adjuvant formulation.

Vaccination can help prevent infection and can also be used to treat cancer, allergy, and potentially even drug overdose. Adjuvants enhance vaccine responses, but currently, the path to their advancement and development is incremental. We used a phenotypic small-molecule screen using THP-1 cells to identify nuclear factor-κB (NF-κB)-activating molecules followed by counterscreening lead target libraries with a quantitative tumor necrosis factor immunoassay using primary human peripheral blood mononuclear cells. Screening on primary cells identified an imidazopyrimidine, dubbed PVP-037. Moreover, while PVP-037 did not overtly activate THP-1 cells, it demonstrated broad innate immune activation, including NF-κB and cytokine induction from primary human leukocytes in vitro as well as enhancement of influenza and SARS-CoV-2 antigen-specific humoral responses in mice. Several de novo synthesis structural enhancements iteratively improved PVP-037's in vitro efficacy, potency, species-specific activity, and in vivo adjuvanticity. Overall, we identified imidazopyrimidine Toll-like receptor-7/8 adjuvants that act in synergy with oil-in-water emulsion to enhance immune responses.

ZBTB11 Depletion Targets Metabolic Vulnerabilities in K-Ras Inhibitor Resistant PDAC.

Over 95% of pancreatic ductal adenocarcinomas (PDAC) harbor oncogenic mutations in K-Ras. Upon treatment with K-Ras inhibitors, PDAC cancer cells undergo metabolic reprogramming towards an oxidative phosphorylation-dependent, drug-resistant state. However, direct inhibition of complex I is poorly tolerated in patients due to on-target induction of peripheral neuropathy. In this work, we develop molecular glue degraders against ZBTB11, a C2H2 zinc finger transcription factor that regulates the nuclear transcription of components of the mitoribosome and electron transport chain. Our ZBTB11 degraders leverage the differences in demand for biogenesis of mitochondrial components between human neurons and rapidly-dividing pancreatic cancer cells, to selectively target the K-Ras inhibitor resistant state in PDAC. Combination treatment of both K-Ras inhibitor-resistant cell lines and multidrug resistant patient-derived organoids resulted in superior anti-cancer activity compared to single agent treatment, while sparing hiPSC-derived neurons. Proteomic and stable isotope tracing studies revealed mitoribosome depletion and impairment of the TCA cycle as key events that mediate this response. Together, this work validates ZBTB11 as a vulnerability in K-Ras inhibitor-resistant PDAC and provides a suite of molecular glue degrader tool compounds to investigate its function.

Integrated single cell analysis reveals co-evolution of malignant B cells and tumor micro-environment in transformed follicular lymphoma.

Histological transformation of follicular lymphoma (FL) to aggressive forms is associated with poor outcome. Phenotypic consequences of this evolution and its impact on the tumor microenvironment (TME) remain unknown. We perform single-cell whole genome sequencing (scWGS) and transcriptome sequencing (scWTS) of 11 paired pre/post-transformation patient samples and scWTS of additional samples from patients without transformation. Our analysis reveals evolutionary dynamics of transformation at single-cell resolution, highlighting a shifting TME landscape, with an emerging immune-cell exhaustion signature, co-evolving with the shifting malignant B phenotype in a regulatory ecosystem. Integration of scWGS and scWTS identifies malignant cell pathways upregulated during clonal tumor evolution. Using multi-color immunofluorescence, we transfer these findings to a TME-based transformation biomarker, subsequently validated in two independent pretreatment cohorts. Taken together, our results provide a comprehensive view of the combined genomic and phenotypic evolution of malignant cells during transformation and shifting crosstalk between malignant cells and the TME.

Randomized study of induction with bendamustine-rituximab ± bortezomib and maintenance with rituximab ± lenalidomide for MCL.

ABSTRACT: Although initial therapy of mantle cell lymphoma (MCL) is not standardized, bendamustine plus rituximab (BR) is commonly used in older patients. Rituximab (R) maintenance after induction is often used. Thus, the open-label, randomized phase 2 ECOG-ACRIN Cancer Research Group E1411 trial was designed to test 2 questions: (1) does addition of bortezomib to BR induction (BVR) and/or (2) addition of lenalidomide to rituximab (LR) maintenance improve progression-free survival (PFS) in patients with treatment-naïve MCL? From 2012 to 2016, 373 previously untreated patients, 87% aged ≥60 years, were enrolled in this trial. At a median follow-up of 7.5 years, there is no difference in the median PFS of BR compared with BVR (5.5 vs 6.4 years; hazard ratio [HR], 0.90; 90% confidence interval [CI], 0.70-1.16). There were no unexpected additional toxicities with BVR treatment compared with BR, with no impact on total dose/duration of treatment received. Independent of the induction treatment, addition of lenalidomide did not significantly improve PFS, with median PFS in R vs LR (5.9 vs 7.2 years; HR, 0.84; 90% CI, 0.62-1.15). Most patients completed the planned 24 cycles of LR at the scheduled dose. In summary, adding bortezomib to BR induction does not prolong PFS in treatment-naïve MCL, and LR maintenance was not associated with longer PFS compared with R alone after BR. Nonetheless, the >5-year median PFS outcomes in this prospective cooperative group trial indicate the efficacy of BR followed by R maintenance as highly effective initial therapy for older patients with MCL. This trial was registered at www.clinicaltrials.gov as #NCT01415752.