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BackgroundClonal immunoglobulin and T-cell receptor rearrangements serve as tumor-specific markers that have become mainstays of the diagnosis and monitoring of lymphoid malignancy. Next-generation sequencing (NGS) techniques targeting these loci have been successfully applied to lymphoblastic leukemia and multiple myeloma for minimal residual disease detection. However, adoption of NGS for primary diagnosis remains limited.MethodsWe addressed the bioinformatics challenges associated with immune cell sequencing and clone detection by designing a novel web tool, CloneRetriever (CR), which uses machine-learning principles to generate clone classification schemes that are customizable, and can be applied to large datasets. CR has 2 applications-a "validation" mode to derive a clonality classifier, and a "live" mode to screen for clones by applying a validated and/or customized classifier. In this study, CR-generated multiple classifiers using 2 datasets comprising 106 annotated patient samples. A custom classifier was then applied to 36 unannotated samples.ResultsThe optimal classifier for clonality required clonal dominance ≥4.5× above background, read representation ≥8% of all reads, and technical replicate agreement. Depending on the dataset and analysis step, the optimal algorithm yielded sensitivities of 81%-90%, specificities of 97%-100%, areas under the curve of 91%-94%, positive predictive values of 92-100%, and negative predictive values of 88%-98%. Customization of the algorithms yielded 95%-100% concordance with gold-standard clonality determination, including rescue of indeterminate samples. Application to a set of unknowns showed concordance rates of 83%-96%.ConclusionsCR is an out-of-the-box ready and user-friendly software designed to identify clonal rearrangements in large NGS datasets for the diagnosis of lymphoid malignancies.

BackgroundOptimum management of low-grade gliomas remains controversial, and widespread practice variation exists. This evidence-based meta-analysis evaluates the association of extent of resection, radiation, and chemotherapy with mortality and progression-free survival at 2, 5, and 10 years in patients with low-grade glioma.MethodsA quantitative systematic review was performed. Inclusion criteria included controlled trials of newly diagnosed low-grade (World Health Organization Grades I and II) gliomas in adults. Eligible studies were identified, assigned a level of evidence for every endpoint considered, and analyzed according to Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. The relative risk of mortality and of progression at 2, 5, and 10 years was calculated for patients undergoing resection (gross total, subtotal, or biopsy), radiation, or chemotherapy.ResultsGross total resection was significantly associated with decreased mortality and likelihood of progression at all time points compared to subtotal resection. Early radiation was not associated with decreased mortality; however, progression-free survival was better at 5 years compared to patients receiving delayed or no radiation. Chemotherapy was associated with decreased mortality at 5 and 10 years in the high-quality literature. Progression-free survival was better at 5 and 10 years compared to patients who did not receive chemotherapy. In patients with isocitrate dehydrogenase 1 gene (IDH1) R132H mutations receiving chemotherapy, progression-free survival was better at 2 and 5 years than in patients with IDH1 wild-type gliomas.ConclusionsResults from this review, the first to quantify differences in outcome associated with surgery, radiation, and chemotherapy in patients with low-grade gliomas, can be used to inform evidence-based management and future clinical trials.

Liquid biopsies collect and analyze tumor components in body fluids, and there is an increasing interest in the investigation of liquid biopsies as a surrogate for tumor tissue in the management of both primary and secondary brain tumors. Herein we critically review available literature on spinal fluid and plasma circulating tumor cells (CTCs) and cell-free tumor (ctDNA) for diagnosis and monitoring of leptomeningeal and parenchymal brain metastases. We discuss technical issues and propose several potential applications of liquid biopsies in different clinical settings (ie, for initial diagnosis, for assessment during treatment, and for guidance of treatment decisions). Last, ongoing clinical studies on CNS metastases that include liquid biopsies are summarized, and recommendations for future clinical studies are provided.

2057 Background: The optimal role of chemotherapy and radiation (RT) in adult low-grade glioma (LGG, WHO grade 1 & 2) is unclear. We conducted a systematic review and study-level meta-analysis of the literature on overall survival (OS) and progression free survival (PFS) in patients with LGG. Methods: Pubmed was queried with MeSH terms. All comparative studies of adults with newly diagnosed, supratentorial LGG were included. Comparisons of interest were OS and PFS at 2, 5, and 10 years in chemotherapy versus no chemotherapy and early RT versus delayed or no RT. Data were extracted from studies and synthesized with a random effects model. Quality of evidence was determined by American Academy of Neurology criteria and further analysis was performed, separating high quality (class I and II) from low quality (class III and IV) evidence. Numbers needed to treat (NNT) were determined from the risk difference. Results: 1531 articles were screened; 18 studies were included. Chemotherapy was not associated with a significant survival advantage compared to control. However, an analysis of high quality data revealed a survival advantage at 10 years associated with chemotherapy compared to control with NNT 5 (relative risk death chemo vs control 0.69 [0.56-0.86] p = 0.0006). Furthermore, NNT to prevent one progression with chemotherapy at 5 and 10 years was 6 and 3, respectively. Early RT was not associated with an OS advantage compared to control. However, early RT had progression benefit at all time points, with NNT of 10, 6, and 5 at 2, 5, and 10 years. Conclusions: Further study will be needed to confirm the optimal role of chemotherapy and RT. Caution must be used in interpretation as much of the literature consists of low-quality studies. [Table: see text]

2025 Background: Low-grade gliomas (LGG) account for 17-22% of all primary brain tumors. Optimal surgical management consists of optimum safe resection with the goal of complete resection. We performed a systematic review and meta-analysis to quantify the association of extent of resection with likelihood of survival, expressing our results in numbers needed to treat (NNT). Methods: A systematic review and study-level meta-analysis to determine the association of resection with overall survival and progression-free survival in newly diagnosed, supratentorial LGG in adults was performed by querying PubMed. Data were extracted to compare gross total resection (GTR) to subtotal resection (STR) and STR to biopsy (Bx) to determine relative risks (RR) of death and progression at 2, 5, and 10 years. Data were analyzed using a random effects model. NNT were calculated from significant comparisons and rounded up to the nearest whole number. Quality of evidence was determined by American Academy of Neurology criteria. Results: The systematic review resulted in 283 potential studies. Ultimately 29 studies were included in at least one comparison. There were no high quality (class I and II) or prospective studies discovered in the review. Comparing GTR to STR, RR with 95% confidence intervals (CI) of death at 2, 5, and 10 years, and NNT to avoid one death at 2, 5, and 10 years (GTR vs. STR) were 0.29 [0.17-0.52, p < 0.0001, NNT 17], 0.39 [0.29-0.51, p < 0.00001, NNT 6], and 0.50 [0.35-0.70, p < 0.0001 NNT 4]. RR and NNT for progression (GTR vs. STR) at 2, 5, and 10 years were 0.37 [0.24-0.57, p < 0.0001 NNT 7], 0.50 [0.39-0.64, p < 0.0001 NNT 4], and 0.67 [0.53-0.84, p = 0.0005 NNT 4]. Comparing STR to Bx, RR of death at 2, 5, and 10 years were 0.55 [0.34-0.88, p = 0.01 NNT 10], 0.9 [0.61-1.34], and 0.95 [0.73-1.23]. Conclusions: Increasing resection thresholds appear to be associated with improved overall and progression free survival, but the body of literature consists of low quality studies. Prospective studies are required to explore whether extent of resection matters or whether resectable tumors share a favorable biology associated with better outcome.

Simple Summary: We identified the TAM (Tyro3, Axl, and MerTK) RTKs as a crucial therapeutic vulnerability in Triple-negative breast cancer (TNBC). We show that targeting the TAM receptors with a novel inhibitor, sitravatinib, significantly sensitizes TNBC to CDK4/6 inhibitors. Given the roles of the TAM receptors in promoting the creation of an immunosuppressive tumor microenvironment (TME), we further demonstrate that the combination of CDK4/6 inhibitor abemaciclib and sitravatinib modifies the immune landscape of TNBC to favor immune checkpoint blockade. Triple-negative breast cancer (TNBC) is the most aggressive subtype with high metastasis and mortality rates. Given the lack of actionable targets such as ER and HER2, TNBC still remains an unmet therapeutic challenge. Despite harboring high CDK4/6 expression levels, the efficacy of CDK4/6 inhibition in TNBC has been limited due to the emergence of resistance. The resistance to CDK4/6 inhibition is mainly mediated by RB1 inactivation. Since our aim is to overcome resistance to CDK4/6 inhibition, in this study, we primarily used the cell lines that do not express RB1. Following a screening for activated receptor tyrosine kinases (RTKs) upon CDK4/6 inhibition, we identified the TAM (Tyro3, Axl, and MerTK) RTKs as a crucial therapeutic vulnerability in TNBC. We show that targeting the TAM receptors with a novel inhibitor, sitravatinib, significantly sensitizes TNBC to CDK4/6 inhibitors. Upon prolonged HER2 inhibitor treatment, HER2+ breast cancers suppress HER2 expression, physiologically transforming into TNBC-like cells. We further show that the combined treatment is highly effective against drug-resistant HER2+ breast cancer as well. Following quantitative proteomics and RNA-seq data analysis, we extended our study into the immunophenotyping of TNBC. Given the roles of the TAM receptors in promoting the creation of an immunosuppressive tumor microenvironment (TME), we further demonstrate that the combination of CDK4/6 inhibitor abemaciclib and sitravatinib modifies the immune landscape of TNBC to favor immune checkpoint blockade. Overall, our study offers a novel and highly effective combination therapy against TNBC and potentially treatment-resistant HER2+ breast cancer that can be rapidly moved to the clinic. [ABSTRACT FROM AUTHOR]

Glioblastomas (GBM) are the most aggressive and prevalent form of gliomas with abysmal prognosis and limited treatment options. We analyzed clinically relevant molecular aberrations suggestive of response to therapies in 1035 GBM tumors. Our analysis revealed mutations in 39 genes of 48 tested. IHC revealed expression of PD-L1 in 19% and PD-1 in 46%. MGMT-methylation was seen in 43%, EGFRvIII in 19% and 1p19q co-deletion in 2%. TP53 mutation was associated with concurrent mutations, while IDH1 mutation was associated with MGMT-methylation and TP53 mutation and was mutually exclusive of EGFRvIII mutation. Distinct biomarker profiles were seen in GBM compared with WHO grade III astrocytoma, suggesting different biology and potentially different treatment approaches. Analysis of 17 metachronous paired tumors showed frequent biomarker changes, including MGMT-methylation and EGFR aberrations, indicating the need for a re-biopsy for tumor profiling to direct subsequent therapy. MGMT-methylation, PR and TOPO1 appeared as significant prognostic markers in sub-cohorts of GBM defined by age. The current study represents the largest biomarker study on clinical GBM tumors using multiple technologies to detect gene mutation, amplification, protein expression and promoter methylation. These data will inform planning for future personalized biomarker-based clinical trials and identifying effective treatments based on tumor biomarkers.

BackgroundMeningioma is the most common extra-axial primary intracranial tumor in adults that rarely metastasizes outside of the central nervous system (CNS). Among recognized sites of metastases, the lung is the most common, but the importance of lung metastases relative to prognosis is unknown. ¹¹¹Indium (¹¹¹In)-octreotide scintigraphy (octreotide scanning) is a valuable imaging modality with which to evaluate intracranial meningiomas and their response to treatment with somatostatin analogues and has the potential to identify extracranial metastatic disease.MethodsIn this retrospective multicenter study, adult patients treated for recurrent meningioma were identified. These patients underwent ¹¹¹In-octreotide positron emission tomography/computed tomography imaging (octreotide scintigraphy) and were found to have positive octreotide uptake in their lungs.ResultsSix cases were identified with recurrent meningioma (after surgery, radiotherapy, and at least 1 chemotherapy agent) and pulmonary lesions by octreotide scintigraphy. Biopsy of a pulmonary lesion in 1 patient confirmed the diagnosis of metastatic meningioma. Patients with metastatic pulmonary involvement identified by ¹¹¹In-octreotide scintigraphy in this case series had an overall survival of 6 months, which is less than that reported from previously published series of patients with unknown systemic disease status.Conclusions¹¹¹In-octreotide scintigraphy is useful for assessing both CNS disease and extracranial metastases. The presence of pulmonary metastases appears to negatively affect survival in patients with recurrent meningioma. The usefulness of ¹¹¹In-octreotide scintigraphy should be considered in staging patients with recurrent meningioma who are considered for further treatment. A prospective study to confirm this finding is warranted

Over the past four decades, people around the globe have experienced unprecedented escalations in the frequency, intensity, magnitude, and location of anomalous hydrometeorological (hydromet) hazards attributed in large measure to the direct and indirect effects of global climate-change-related variability and extremes. The WMO, impelled by an unabated warming of the global climate system and its related extremely anomalous hydromet impacts, chose in March 2022 "Early Warning, Early Action" (EWEA) as the theme for its World Meteorology Day. The theme was praised in a press release by UN Secretary-General Antonio Guterres, who called for the development of a new EWEA initiative to ensure that "every person on Earth is protected by early warning systems within five years". By mid-2022, several meetings and workshops had already been held by the WMO to forge the new initiative on its road to the UN Climate Conference of Parties (COP27) in November in Sharm El Sheikh, Egypt. COP27 provided a suitably prominent venue for launching the new USD 3.1 billion, 5-year EWEA initiative; there, Secretary-General Guterres formally tasked the WMO, in partnership with the UNDRR, to lead it. But COP27 proved to be interesting as well as illuminating in other, less publicized ways having to do with EWEA. There, what had been the working title of the new initiative was officially changed to EW4A, "Early Warning for All". Despite the seemingly perfunctory nature of this change, the reality is that it will almost certainly have outsized impacts on the strengths, weaknesses, opportunities, and constraints (SWOC) met specifically in planning and implementing the new initiative's "early action" strategies and tactics. It is particularly important to bear in mind that, as things now stand, various unanticipated challenges having to do with the lack of organizational experience and capacity with regard to "early action" are likely to arise with the WMO-led implementation of the new initiative. Considering the new EW4A acronym as if it was a commercial brand can, like this, be instructive in thinking about how the seemingly perfunctory name change—from EWEA to EW4A—will impact the initiative's implementation of "early action". Doing so can be instructive because, just as the logos of companies like Apple, Nike, or Starbucks eventually became the face of their respective products, so too have branded acronyms like NASA, IOC, WHO, and INTERPOL become the face of their governmental institutions' or global initiatives' respective commissions and commitments. It follows then that if "consumer" interest is to be taken seriously and is (hopefully) long-lasting, then the branding of a new product or initiative must be undertaken with great consideration before a final identifier—be it a logo, a catchphrase, or an acronym—is selected. The question in the case of the new WMO-led initiative, then, is the following: Was this issue seriously taken into consideration before EWEA was so abruptly replaced by EW4A at COP27 in Egypt in November 2022? This pointed question is especially meant to highlight how the continued use of the original EWEA acronym by way of developing regional EWEA centers under the "Early Warning for All" umbrella has the possibility of turning regional potential energy into kinetic energy which will be essential if the theoretical gains of future "early warning" (EW) forecasting science are to be effectively translated into "early action" (EA) strategies and tactics that actually, finally, protect people and property across the entirety of the earth from the impending severe impacts of our changing climate future. Thus does this paper raise valid concerns about the balance between support and funding for EW and EA. [ABSTRACT FROM AUTHOR]