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Development and Validation of a Clinical Risk Model for Postoperative Outcome in Newly Diagnosed Glioblastoma: A Report of the RANO Resect Group
Get PDFBackground: Following surgery, patients with newly diagnosed glioblastoma frequently enter clinical trials. Nuanced risk assessment is warranted to reduce imbalances between study arms. Here, we aimed (I) to analyze the interactive effects of residual tumor with clinical and molecular factors on outcome and (II) to define a postoperative risk assessment tool.
Methods: The response assessment in neuro-oncology (RANO) resect group retrospectively compiled an international, seven-center training cohort of patients with newly diagnosed glioblastoma. The combined associations of residual tumor with molecular or clinical factors and survival were analyzed, and recursive partitioning analysis was performed for risk modeling. The resulting model was prognostically verified in a separate external validation cohort.
Results: Our training cohort compromised 1003 patients with newly diagnosed isocitrate dehydrogenase-wildtype glioblastoma. Residual tumor, O6-methylguanine DNA methyltransferase (MGMT) promotor methylation status, age, and postoperative Karnofsky Performance Score were prognostic for survival and incorporated into regression tree analysis. By individually weighting the prognostic factors, an additive score (range, 0-9 points) integrating these four variables distinguished patients with low (0-2 points), intermediate (3-5 points), and high risk (6-9 points) for inferior survival. The prognostic value of our risk model was retained in treatment-based subgroups and confirmed in an external validation cohort of 258 patients with glioblastoma. Compared to previously postulated models, goodness-of-fit measurements were superior for our model.
Conclusions: The novel RANO risk model serves as an easy-to-use, yet highly prognostic tool for postoperative patient stratification prior to further therapy. The model may serve to guide patient management and reduce imbalances between study arms in prospective trials
Vasa Previa: Prenatal Diagnosis and the Rationale Behind Using a 5 cm Distance from Internal Os
No full textIn pregnancies with vasa previa, prenatal diagnosis and pre-labor cesarean delivery are associated with significantly improved perinatal outcomes compared to undetected cases. However, a universally accepted ultrasonographic definition of vasa previa is lacking. Specifically, the distance from the cervical internal os beyond which vaginal delivery can be safely recommended remains to be determined. Field experts and recently published societal guidelines agree that a 2 cm cut-off is suboptimal, given that complete cervical dilation during labor risks unprotected fetal vessels within a 5 cm radius from the internal os. Thus, in the setting of a scarcity of evidence and case reports of perinatal death with unprotected fetal vessels beyond 2 cm from the internal os, a more conservative definition that includes unprotected fetal vessels located within 5 cm of the internal os is imperative to improve outcomes
Cryptic KMT2A::AFDN Fusion Due to AFDN Insertion into KMT2A in a Patient with Acute Monoblastic Leukemia
Get PDFBackground: KMT2A rearrangements occur in ~10% of acute myeloid leukemia (AML) cases and are critical for classification, risk stratification, and use of targeted therapy. However, insertions involving the KMT2A gene can evade detection using chromosomal analysis and/or fluorescence in situ hybridization (FISH).
Methods: We present a case of a 22-year-old woman with acute monoblastic leukemia harboring a cryptic KMT2A::AFDN fusion identified by RNA sequencing. Initial FISH showed a 3\u27 KMT2A deletion, while conventional karyotyping and the automated bioinformatic pipeline for optical genome mapping (OGM) did not identify the canonical translocation.
Results: To resolve these discrepancies, metaphase KMT2A FISH (break-apart fusion probe) was performed to assess whether KMT2A was translocated to another chromosome. However, the results did not support this possibility. As the fusion signal remained on the normal chromosome 11, with the 5\u27 KMT2A signal localized to the derivative chromosome 11. A subsequent manual review of the OGM data revealed a cryptic ~300 kb insertion of AFDN into the 3\u27 region of KMT2A, reconciling the discrepancies between chromosomal analysis, FISH, and RNA fusion results.
Conclusions: This case highlights the importance of integrating multiple testing modalities with expert review when there is a discrepancy. Our findings emphasize the need for a comprehensive approach to genomic assessment to enhance diagnostic accuracy and guide therapeutic decision-making
Long Term Results of Venetoclax Combined With FLAG-IDA Induction and Consolidation for Newly Diagnosed and Relapsed or Refractory Acute Myeloid Leukemia
No full textIntensive chemotherapy remains the standard for newly diagnosed (ND) acute myeloid leukemia (AML); however, relapse risk remains high. Additionally, most patients with relapsed/refractory (RR) AML have poor outcomes. We report the long-term experience of 138 patients, 77 ND and 61 RR, treated with FLAG-IDA in combination with venetoclax. In the ND cohort, the overall response rate (ORR) was 97%, with a composite complete remission (CRc) rate of 95% and undetectable measurable residual disease (MRD) status by flow cytometry in 90%. The 3-year OS and EFS rates were 66 and 64%, respectively. Outcomes were similar across European LeukemiaNet (ELN) 2022 risk groups. Sixty-four percent transitioned to allogeneic hematopoietic stem cell transplantation (allo-SCT) in CR1. In the RR cohort, the ORR was 67%; CRc rate 41% and flow negative MRD rate 74%; 57% transitioned to allo-SCT. The patients with RR AML in first salvage with wild-type TP53 status had particularly favorable outcomes, with an ORR of 79%, CRc rate of 74% (76% MRD undetectable) and 3-year OS rate of 51%. Infectious and hematologic adverse events were common, with low 30- and 60-day mortality similar to other intensive chemotherapy regimens. FLAG-IDA + VEN is effective for remission induction in both ND and RR AML.ClinicalTrials.gov Identifier: NCT03214562
Lifespan Reference Curves for Harmonizing Multi-site Regional Brain White Matter Metrics From Diffusion MRI
No full textAge-related white matter (WM) microstructure maturation and decline occur throughout the human lifespan, complementing the process of gray matter development and degeneration. Here, we create normative lifespan reference curves for global and regional WM microstructure by harmonizing diffusion MRI (dMRI)-derived data from ten public datasets (N = 40,898 subjects; age: 3-95 years; 47.6% male). We tested three harmonization methods on regional diffusion tensor imaging (DTI) based fractional anisotropy (FA), a metric of WM microstructure, extracted using the ENIGMA-DTI pipeline. ComBat-GAM harmonization provided multi-study trajectories most consistent with known WM maturation peaks. Lifespan FA reference curves were validated with test-retest data and used to assess the effect of the ApoE4 risk factor for dementia in WM across the lifespan. We found significant associations between ApoE4 and FA in WM regions associated with neurodegenerative disease even in healthy individuals across the lifespan, with regional age-by-genotype interactions. Our lifespan reference curves and tools to harmonize new dMRI data to the curves are publicly available as eHarmonize ( https://github.com/ahzhu/eharmonize )
Intersect Between Brain Mechanisms of Conditioned Threat, Active Avoidance, and Reward
No full textActive avoidance is a core behavior for human coping, and its excess is common across psychiatric diseases. The decision to actively avoid a threat is influenced by cost and reward. Yet, threat, avoidance, and reward have been studied in silos. We discuss behavioral and brain circuits of active avoidance and the interactions with fear and threat. In addition, we present a neural toggle switch model enabling fear-to-anxiety transition and approaching reward vs. avoiding harm decision. To fully comprehend how threat, active avoidance, and reward intersect, it is paramount to develop one shared experimental approach across phenomena and behaviors, which will ultimately allow us to better understand human behavior and pathology
Epigenome-Wide DNA Methylation Association Study of Chip Provides Insight Into Perturbed Gene Regulation
No full textWith age, hematopoietic stem cells can acquire somatic mutations in leukemogenic genes that confer a proliferative advantage in a phenomenon termed CHIP. How these mutations result in increased risk for numerous age-related diseases remains poorly understood. We conduct a multiracial meta-analysis of EWAS of CHIP in the Framingham Heart Study, Jackson Heart Study, Cardiovascular Health Study, and Atherosclerosis Risk in Communities cohorts (N = 8196) to elucidate the molecular mechanisms underlying CHIP and illuminate how these changes influence cardiovascular disease risk. We functionally validate the EWAS findings using human hematopoietic stem cell models of CHIP. We then use expression quantitative trait methylation analysis to identify transcriptomic changes associated with CHIP-associated CpGs. Causal inference analyses reveal 261 CHIP-associated CpGs associated with cardiovascular traits and all-cause mortality (FDR adjusted p-value \u3c 0.05). Taken together, our study reports the epigenetic changes impacted by CHIP and their associations with age-related disease outcomes
In Vitro Hydrolysis of Areca Nut Xenobiotics in Human Liver
No full textAreca nut (AN) is a substance of abuse consumed by millions worldwide, in spite of established oral and systemic toxicities associated with its use. Previous research demonstrates methyl ester alkaloids in the AN, such as arecoline and guvacoline, exhibit mood-altering and toxicological effects. Nonetheless, their metabolism has not been fully elucidated in humans. In the present study, an HPLC-UV bioanalytical method was developed to evaluate the hydrolytic kinetics and clearance rates of arecoline and guvacoline in human liver microsomes (HLM) and cytosol (HLC). The bioassay was capable of quantifying arecoline and guvacoline (and carboxylate metabolites arecaidine and guvacine, respectively) with good sensitivity, accuracy, and precision. Kinetics of arecoline and guvacoline hydrolysis best followed the Michaelis-Menten model. Apparent intrinsic clearance (Clint.in vivo) of arecoline was 57.8 ml/min/kg in HLM and 11.6 mL/min/kg in HLC, a 5-fold difference. Unexpectedly, guvacoline was dramatically less hydrolyzed than arecoline in both HLM and HLC, with Clint.in vivo estimates of 0.654 ml/min/kg and 0.466 ml/min/kg, respectively. These results demonstrate, for the first time, arecoline undergoes significant hydrolysis with high clearance rates in the liver. Furthermore, differential tissue metabolic rates and utilization of specific esterase inhibitors unequivocally demonstrated arecoline is a substrate for CES1 and not CES2
RUNX2 Is Essential for Maintaining Synchondrosis Chondrocytes and Cranial Base Growth
No full textThe cranial base synchondroses, comprised of opposite-facing bidirectional chondrocyte layers, drive anteroposterior cranial base growth. In humans, RUNX2 haploinsufficiency causes cleidocranial dysplasia associated with deficient midfacial growth. However, how RUNX2 regulates chondrocytes in the cranial base synchondroses remains unknown. To address this, we inactivated Runx2 in postnatal synchondrosis chondrocytes using a tamoxifen-inducible Fgfr3-creER (Fgfr3-Runx2cKO) mouse model. Fgfr3-Runx2cKO mice displayed skeletal dwarfism and reduced anteroposterior cranial base growth associated with premature synchondrosis ossification due to impaired chondrocyte proliferation, accelerated hypertrophy, apoptosis, and osteoclast-mediated cartilage resorption. Lineage tracing reveals that Runx2-deficient Fgfr3+ cells failed to differentiate into osteoblasts. Notably, Runx2-deficient chondrocytes showed an elevated level of FGFR3 and its downstream signaling components, pERK1/2 and SOX9, suggesting that RUNX2 downregulates FGFR3 in the synchondrosis. This study unveils a new role of Runx2 in cranial base chondrocytes, identifying a possible RUNX2-FGFR3-MAPK-SOX9 signaling axis that may control cranial base growth
The Influence of Tobacco Use, Hazardous Drinking, and Other Risk Factors on HPV-Associated Oropharyngeal Cancer Risk and Screening Perceptions Among Gay and Bisexual Men: A Cross-Sectional Study
No full textBackground: Oropharyngeal cancer is the eighth most common cancer among US men and its incidence is sharply rising. Oropharyngeal cancer manifests in two major ways: the classic form is prevalent among people who use alcohol and tobacco heavily, while a growing subset of incident cases is associated with human papillomavirus-16 (HPV) and transmitted via oral sex. Gay and bisexual men appear at higher risk for each etiologic subset of oropharyngeal cancer than heterosexual men. We conducted a cross-sectional study to learn how tobacco use, hazardous drinking, and other key risk factors affect gay and bisexual men\u27s perceptions of oropharyngeal cancer risk and beliefs about screening at a doctor\u27s office and self-screening at home.
Methods: We recruited 1,699 gay and bisexual men from two dating websites to participate in an online survey. We asked about tobacco use, alcohol consumption, sexual history, and other risk factors for oropharyngeal cancer. The survey also investigated participants\u27 perceptions of oropharyngeal cancer risk and potential worry related to screening. We analyzed results at the bivariate level and in multivariable regression models. We used logistic regression to analyze categorical data and linear regression to analyze continuous data.
Results: Average age of participants was 41.5 (SD = 12.7) years. Most were cisgender (95%), and identified as gay (80%), while 19% were bisexual or pansexual, with 2% reporting being queer or a self-described sexuality. Factors associated with high perceived oropharyngeal cancer risk perceptions were cigarette smoking, using both cigarettes and vaping, being gay identified, number of sexual partners in the last 12 months, and having poor mouth/teeth condition. Factors associated with oropharyngeal cancer screening worry were being Hispanic, having queer/self-described sexuality, not having health insurance, and having poor mouth/teeth condition. No factors were associated with self-screening at home. Alcohol use was not associated with oropharyngeal cancer risk perception.
Conclusions: This study examines oropharyngeal cancer risk perceptions among gay and bisexual men. Health promotion efforts to reduce oropharyngeal cancer risk among gay and bisexual men should involve comprehensive oral health, sexual health, and tobacco use education. Researchers should continue investigating acceptable and effective home self-screening methods for HPV-associated cancers