tbuckley/cabot-search huggingface dataset:
Cancer stem cell hypothesis 2.0 in glioblastoma: Where are we now and where are we going?
Authors: Anthony R Sloan, Daniel J Silver, Sam Kint, Marco Gallo, Justin D Lathia
Journal: Neuro-Oncology (2024)

Abstract Over the past 2 decades, the cancer stem cell (CSC) hypothesis has provided insight into many malignant tumors, including glioblastoma (GBM). Cancer stem cells have been identified in patient-derived tumors and in some mouse models, allowing for a deeper understanding of cellular and molecular mechanisms underlying GBM growth and therapeutic resistance. The CSC hypothesis has been the cornerstone of cellular heterogeneity, providing a conceptual and technical framework to explain this longstanding phenotype in GBM. This hypothesis has evolved to fit recent insights into how cellular plasticity drives tumor growth to suggest that CSCs do not represent a distinct population but rather a cellular state with substantial plasticity that can be achieved by non-CSCs under specific conditions. This has further been reinforced by advances in genomics, including single-cell approaches, that have used the CSC hypothesis to identify multiple putative CSC states with unique properties, including specific developmental and metabolic programs. In this review, we provide a historical perspective on the CSC hypothesis and its recent evolution, with a focus on key functional phenotypes, and provide an update on the definition for its use in future genomic studies.
Tyrosine kinase inhibitor response of ABL-class acute lymphoblastic leukemia: the role of kinase type and SH3 domain
Authors: Inge van Outersterp, Sarah K. Tasian, Caitlin E. J. Reichert, Aurélie Boeree, Hester A. de Groot-Kruseman, Gabriele Escherich, Judith M. Boer, Monique L. den Boer
Journal: Blood (2024)

Acute lymphoblastic leukemia (ALL) with fusions of ABL-class tyrosine kinase genes other than BCR::ABL1 occurs in ∼3% of children with ALL. The tyrosine kinase genes involved in this BCR::ABL1-like (Ph-like) subtype include ABL1, PDGFRB, ABL2, and CSF1R, each of which has up to 10 described partner genes. ABL-class ALL resembles BCR::ABL1-positive ALL with a similar gene expression profile, poor response to chemotherapy, and sensitivity to tyrosine kinase inhibitors (TKIs). There is a lack of comprehensive data regarding TKI sensitivity in the heterogeneous group of ABL-class ALL. We observed variability in TKI sensitivity within and among each ABL-class tyrosine kinase gene subgroup. We showed that ALL samples with fusions for any of the 4 tyrosine kinase genes were relatively sensitive to imatinib. In contrast, the PDGFRB-fused ALL samples were less sensitive to dasatinib and bosutinib. Variation in ex vivo TKI response within the subset of samples with the same ABL-class tyrosine kinase gene was not associated with the ALL immunophenotype, 5' fusion partner, presence or absence of Src-homology-2/3 domains, or deletions of IKZF1, PAX5, or CDKN2A/B. In conclusion, the tyrosine kinase gene involved in ABL-class ALL is the main determinant of TKI sensitivity and relevant for specific TKI selection.
Daratumumab, carfilzomib, lenalidomide, and dexamethasone with tandem transplant for high-risk newly diagnosed myeloma
Authors: Cyrille Touzeau, Aurore Perrot, Cyrille Hulin, Salomon Manier, Margaret Macro, Marie-Lorraine Chretien, Lionel Karlin, Martine Escoffre, Caroline Jacquet, Mourad Tiab, Xavier Leleu, Herve Avet-Loiseau, Alexandra Jobert, Lucie Planche, Jill Corre, Philippe Moreau
Journal: Blood (2024)

High-risk (HR) cytogenetics are associated with poor outcomes in newly diagnosed multiple myeloma (NDMM), and dedicated studies should address this difficult-to-treat population. The phase 2 study 2018-04 from the Intergroupe Francophone du Myelome evaluated feasibility of an intensive strategy with quadruplet induction and consolidation plus tandem transplant in HR transplant-eligible (TE) NDMM. HR cytogenetics were defined by presence of del(17p), t(4;14), and/or t(14;16). Treatment consisted of daratumumab-carfilzomib-lenalidomide-dexamethasone (D-KRd) induction, autologous stem cell transplantation (ASCT), D-KRd consolidation, second ASCT, and daratumumab-lenalidomide maintenance. The primary end point was feasibility. Fifty patients with previously untreated NDMM were included. Median age was 57. Del(17p), t(4;14), and t(14;16) were found in 40%, 52%, and 20% of patients, respectively. At data cutoff, the study met the primary end point with 36 patients completing second transplant. Twenty patients discontinued the study due to stem cell collection failure (n = 8), disease progression (n = 7), adverse event (n = 4), or consent withdrawal (n = 1). Grade 3 to 4 D-KRd induction/consolidation-related adverse events (>5% of patients) were neutropenia (39%), anemia (12%), thrombocytopenia (7%), and infection (6%). The overall response rate was 100% for patients completing second transplant, including 81% complete response. Premaintenance minimal residual disease (MRD) negativity rate (10-6) was 94%. After a median follow-up of 33 months, the 30-month progression-free survival (PFS) and overall survival were 80% and 91%, respectively. In conclusion, D-KRd with tandem transplant is feasible in patients with HR TE-NDMM and resulted in high response rates and PFS. This trial was registered at www.clinicaltrials.gov as #NCT03606577.
Mitochondrial DNA competition: starving out the mutant genome
Authors: Antonella Spinazzola, Diego Perez-Rodriguez, Jan Ježek, Ian J. Holt
Journal: Trends in Pharmacological Sciences (2024)

High levels of pathogenic mitochondrial DNA (mtDNA) variants lead to severe genetic diseases, and the accumulation of such mutants may also contribute to common disorders. Thus, selecting against these mutants is a major goal in mitochondrial medicine. Although mutant mtDNA can drift randomly, mounting evidence indicates that active forces play a role in the selection for and against mtDNA variants. The underlying mechanisms are beginning to be clarified, and recent studies suggest that metabolic cues, including fuel availability, contribute to shaping mtDNA heteroplasmy. In the context of pathological mtDNAs, remodeling of nutrient metabolism supports mitochondria with deleterious mtDNAs and enables them to outcompete functional variants owing to a replicative advantage. The elevated nutrient requirement represents a mutant Achilles' heel because small molecules that restrict nutrient consumption or interfere with nutrient sensing can purge cells of deleterious mtDNAs and restore mitochondrial respiration. These advances herald the dawn of a new era of small-molecule therapies to counteract pathological mtDNAs.
Efficient gene delivery by multifunctional star poly (β-amino ester)s into difficult-to-transfect macrophages for M1 polarization
Authors: Tao Bo, Chenfei Wang, Dingjin Yao, Qiuyu Jiang, Yitong Zhao, Feifei Wang, Wei He, Weiyi Xu, Hao Zhou, Ming Li, Si Zhang, Ruyi Xue
Journal: Journal of Controlled Release (2024)
Waking Up to the Importance of Sleep in Type 2 Diabetes Management: A Narrative Review
Authors: Joseph Henson, Alix Covenant, Andrew P. Hall, Louisa Herring, Alex V. Rowlands, Thomas Yates, Melanie J. Davies
Journal: Diabetes Care (2024)

For the first time, the latest American Diabetes Association/European Association for the Study of Diabetes (ADA/EASD) consensus guidelines have incorporated a growing body of evidence linking health outcomes associated with type 2 diabetes to the movement behavior composition over the whole 24-h day. Of particular note, the importance of sleep as a key lifestyle component in the management of type 2 diabetes is promulgated and presented using three key constructs: quantity, quality, and timing (i.e., chronotype). In this narrative review we highlight some of the key evidence justifying the inclusion of sleep in the latest consensus guidelines by examining the associations of quantity, quality, and timing of sleep with measures of glycemia, cardiovascular disease risk, and mortality. We also consider potential mechanisms implicated in the association between sleep and type 2 diabetes and provide practical advice for health care professionals about initiating conversations pertaining to sleep in clinical care. In particular, we emphasize the importance of measuring sleep in a free-living environment and provide a summary of the different methodologies and targets. In summary, although the latest ADA/EASD consensus report highlights sleep as a central component in the management of type 2 diabetes, placing it, for the first time, on a level playing field with other lifestyle behaviors (e.g., physical activity and diet), the evidence base for improving sleep (beyond sleep disorders) in those living with type 2 diabetes is limited. This review should act as a timely reminder to incorporate sleep into clinical consultations, ongoing diabetes education, and future interventions.
A Diabetes Pregnancy Technology Roadmap: The 2023 Norbert Freinkel Award Lecture
Authors: Helen R. Murphy
Journal: Diabetes Care (2024)

Norbert Freinkel emphasized the need for “more aggressive therapy with exogenous insulin” during type 1 diabetes (T1D) pregnancy. Recent advances in diabetes technology, continuous glucose monitoring (CGM), and hybrid closed-loop (HCL) insulin delivery systems allow us to revisit Freinkel’s observations from a contemporary perspective. The Continuous Glucose Monitoring in Women With Type 1 Diabetes in Pregnancy Trial (CONCEPTT) led to international recommendations that CGM be offered to all pregnant women with T1D to help them meet their pregnancy glucose targets and improve neonatal outcomes. However, despite CGM use, only 35% of trial participants reached the pregnancy glucose targets by 35 weeks’ gestation, which is too late for optimal obstetric and neonatal outcomes. The constant vigilance to CGM data and insulin dose adjustment, with perpetual worry about the impact of hyperglycemia on the developing fetal structures, leave many pregnant women feeling overwhelmed. HCL systems that can adapt to marked gestational changes in insulin sensitivity and pharmacokinetics may help to bridge the gap between the nonpregnant time in range glycemic targets (70–180 mg/dL) and the substantially more stringent pregnancy-specific targets (TIRp) (63–140 mg/dL) required for optimal obstetric and neonatal outcomes. Use of HCL (CamAPS FX system) was associated with a 10.5% higher TIRp, 10.2% less hyperglycemia, and 12.3% higher overnight TIRp. Clinical benefits were accompanied by 3.7 kg (8 lb) less gestational weight gain and consistently achieved across a representative patient population of insulin pump or injection users, across trial sites, and across maternal HbA1c categories. Working collaboratively, women, HCL technology, and health care teams achieved improved glycemia with less worry, less work, and more positive pregnancy experiences.
NCCN Guidelines® Insights: Kidney Cancer, Version 2.2024
Authors: Robert J. Motzer, Eric Jonasch, Neeraj Agarwal, Ajjai Alva, Hilary Bagshaw, Michael Baine, Kathryn Beckermann, Maria I. Carlo, Toni K. Choueiri, Brian A. Costello, Ithaar H. Derweesh, Arpita Desai, Yasser Ged, Saby George, John L. Gore, Andrew Gunn, Naomi Haas, Michael Johnson, Payal Kapur, Jennifer King, Christos Kyriakopoulos, Elaine T. Lam, Primo N. Lara, Clayton Lau, Bryan Lewis, David C. Madoff, Brandon Manley, M. Dror Michaelson, Amir Mortazavi, Lee Ponsky, Sundhar Ramalingam, Brian Shuch, Zachary L. Smith, Jeffrey Sosman, Randy Sweis, Matthew Zibelman, Ryan Schonfeld, MaryElizabeth Stein, Lisa A. Gurski
Journal: Journal of the National Comprehensive Cancer Network (2024)

The NCCN Guidelines for Kidney Cancer provide multidisciplinary recommendations for diagnostic workup, staging, and treatment of patients with renal cell carcinoma (RCC). These NCCN Guidelines Insights focus on the systemic therapy options for patients with advanced RCC and summarize the new clinical data evaluated by the NCCN panel for the recommended therapies in Version 2.2024 of the NCCN Guidelines for Kidney Cancer.
Navigating the Management of Chronic Phase CML in the Era of Generic BCR::ABL1 Tyrosine Kinase Inhibitors
Authors: Fadi G. Haddad, Hagop Kantarjian
Journal: Journal of the National Comprehensive Cancer Network (2024)

Over the past several years, advances in research, treatment, and market dynamics have impacted treatment strategies in chronic myeloid leukemia in chronic phase (CML-CP). They include the broader availability of cost-effective generic imatinib, and soon other generic second-generation tyrosine kinase inhibitors (TKIs). Access to affordable generics means that all patients with CML-CP should have access to safe and highly effective lifelong therapies. When overall survival is the treatment endpoint, imatinib provides a good treatment value. Second-generation TKIs may be the best frontline strategy when treatment-free remission is the goal. Recent studies have shown maintained efficacy and reduced toxicity when TKIs are used at reduced dosing. Reduced-dose schedules of second-generation TKIs (which are less toxic and induce faster deep molecular responses) may render generic second-generation TKIs a more attractive treatment option. Adjusting the dose of TKI in the presence of mild-to-moderate, or even severe but reversible, adverse events may be preferable to switching to a different TKI. The selection of second-line and beyond therapies depends on the evolving patterns observed with frontline treatment. Dose-adjusted ponatinib schedules have demonstrated improved efficacy and safety in patients resistant to second-generation TKIs or those with T315I-mutated disease. For asciminib, longer-term follow-up is needed to better evaluate its safety and efficacy compared with ponatinib. Allogeneic stem cell transplantation represents a valid alternative to newer-generation TKIs, with a better treatment value when TKIs are priced at >$40,000/year.
Value of Size and Malignant Features of Lateral Lymph Nodes in Risk Stratification at Lateral Local Recurrence of Rectal Cancer: A National Cohort Study
Authors: Eline G.M. van Geffen, Tania C. Sluckin, Sanne-Marije J.A. Hazen, Karin Horsthuis, Regina G.H. Beets-Tan, Susan van Dieren, Corrie A.M. Marijnen, Pieter J. Tanis, Miranda Kusters
Journal: Journal of the National Comprehensive Cancer Network (2024)

Background: Patients with rectal cancer who have enlarged lateral lymph nodes (LLNs) have an increased risk of lateral local recurrence (LLR). However, little is known about prognostic implications of malignant features (internal heterogeneity, irregular margins, loss of fatty hilum, and round shape) on MRI and number of enlarged LLNs, in addition to LLN size. Methods: Of the 3,057 patients with rectal cancer included in this national, retrospective, cross-sectional cohort study, 284 with a cT3–4 tumor located ≤8 cm from the anorectal junction who received neoadjuvant treatment and who had visible LLNs on MRI were selected. Imaging was reassessed by trained radiologists. LLNs were categorized based on size. Influence of malignant features and the number of LLNs on LLR was investigated. Results: Of 284 patients with at least 1 visible LLN, 122 (43%) had an enlarged node (≥7.0 mm) and 157 (55%) had malignant features. Of the 122 patients with enlarged nodes, 25 had multiple (≥2). In patients with a single enlarged node (n=97), a single malignant feature was associated with a 4-year LLR rate of 0% and multiple malignant features was associated with a rate of 17% ( P =.060). In the group with multiple malignant features, their disappearance on restaging was associated with an LLR rate of 13% compared with an LLR rate of 20% for persistent malignant features ( P =.532). The presence of intermediate-size LLNs (5.0–6.9 mm) with at least 1 malignant feature was associated with a 4-year LLR rate of 8%; the 4-year LLR rate was 13% when the malignant features persisted on restaging MRI ( P =.409). Patients with multiple enlarged LLNs had a 4-year LLR rate of 28% compared with 11% for those with a single enlarged LLN ( P =.059). Conclusions: The presence of multiple enlarged LLNs (≥7.0 mm), as well as multiple malignant features in an enlarged node contribute to the risk of developing an LLR. These radiologic features can be used for clinical decision-making regarding the potential benefit of LLN dissection.
Disparities in Survival and NCCN Guideline–Concordant Care in Patients With Extremity Soft Tissue Sarcoma
Authors: Hayley M. Dunlop, Bence Bende, Samantha M. Ruff, Alex Kim, James L. Fisher, Valerie P. Grignol, Carlo M. Contreras, Samilia Obeng-Gyasi, David J. Konieczkowski, Timothy M. Pawlik, Raphael E. Pollock, Joal D. Beane
Journal: Journal of the National Comprehensive Cancer Network (2024)

Background: Based on the NCCN Guidelines for Soft Tissue Sarcoma (STS), treatment of extremity STS (ESTS) includes radiation therapy (RT) and surgical resection for tumors that are high-grade and &gt;5 cm. ​​The aim of this study was to describe the association between neighborhood socioeconomic status (nSES), concordance with NCCN Guidelines recommendations, and outcomes in patients with ESTS. Methods: Patients with ESTS diagnosed from 2006 through 2018 were identified in SEER registries. The analytic cohort was restricted to patients with high-grade tumors &gt;5 cm without nodal or distant metastases who received limb-sparing surgery. Patient demographics and tumor characteristics associated with receipt of RT were analyzed using adjusted regression analyses. Kaplan-Meier curves and adjusted accelerated failure time models were used to examine disparities in cancer-specific survival. Results: Of 2,249 patients, 29.0% (n=648) received neoadjuvant RT, 49.7% (n=1,111) received adjuvant or intraoperative RT, and 21.3% (n=476) did not receive RT. In adjusted analyses, lower nSES was associated with lower likelihood of receiving RT (odds ratio, 0.70 [95% CI, 0.57–0.87]; P &lt;.001). Low nSES was associated with worse cancer-specific survival (hazard ratio, 1.19 [95% CI, 1.01–1.40]; P =.04). Race and ethnicity were not significant predictors of receipt of RT or cancer-specific survival in the fully adjusted models. Conclusions: Patients from lower nSES areas were less likely to receive NCCN Guideline–recommended RT for their ESTS and had worse cancer-specific survival. Efforts to better define and resolve disparities in the treatment and survival of patients with ESTS are warranted.
Group Coping Intervention in Patients With Chronic Graft-Versus-Host Disease: A Pilot Randomized Clinical Trial
Authors: Ashley M. Nelson, Daniel Yang, Annemarie D. Jagielo, Jennifer D’Alotto, Cathleen Poliquin, Dustin J. Rabideau, Katherine G. Cronin, Richard A. Newcomb, Yi-Bin Chen, Zachariah DeFilipp, Joseph A. Greer, Areej El-Jawahri, Lara Traeger
Journal: Journal of the National Comprehensive Cancer Network (2024)

Background: More than half the long-term survivors of allogeneic hematopoietic cell transplantation develop chronic graft-versus-host disease (GVHD), a debilitating inflammatory syndrome. Supportive interventions to assist survivors in coping with chronic GVHD are critically needed. Patients and Methods: We conducted a pilot randomized clinical trial of a multidisciplinary group intervention (Horizons Program; n=39) versus minimally enhanced usual care (n=41) for patients with moderate or severe chronic GVHD. Horizons participants received 8 weekly sessions about GVHD and coping co-led by a transplant clinician and a behavioral health expert via a secure videoconferencing platform. Participants completed the following surveys before randomization, at 10 weeks, and at 18 weeks: Functional Assessment of Cancer Therapy–Bone Marrow Transplant Scale (FACT-BMT) for quality of life (QoL), Lee Symptom Scale for symptom burden, and Hospital Anxiety and Depression Scale–Depression Symptoms (HADS) for mood. The primary endpoint was feasibility (≥50% enrollment, ≥80% attendance in half the sessions for the Horizons arm only, and ≥80% retention). We also explored preliminary efficacy of the Horizons intervention on changes in patient-reported outcomes with linear mixed effects models and estimates of effect size at 10 weeks. Results: We enrolled and registered 80 (67.2%) of 119 eligible patients (mean age, 62 years; 48.8% female). Of the participants in the Horizons Program, 84.6% attended at least half the sessions. Of registered participants, 91.3% completed assessment follow-ups (Horizons, 35/39 [89.7%]; minimally enhanced usual care, 38/41 [92.7%]). Horizons participants reported improvements in QoL ( b = 2.24; d =0.53), anxiety symptoms ( b = –0.10; d =0.34), and depression symptoms ( b = –0.71; d =0.44) compared with participants who received minimally enhanced usual care. Conclusions: Participation in a multidisciplinary group intervention study was feasible for patients with chronic GVHD, with promising signals for improving QoL and mood. A full-scale efficacy trial is needed to confirm effects on patient-reported outcomes.
Association Between Alcohol Use Disorder and Hospital Readmission Rates and Outcomes in Cancer Survivors: A Population Cohort Study
Authors: Jyun-Heng Lai, Sola Han, Chanhyun Park, Anton L.V. Avanceña
Journal: Journal of the National Comprehensive Cancer Network (2024)

Background: Alcohol use disorder (AUD) is the most common substance use disorder and is characterized by heavy alcohol use and the inability to control drinking. This study sought to compare the rate, timing, length, and total costs of hospital readmissions among cancer survivors with and without AUD. Methods: We used the Nationwide Readmissions Database in 2017 and 2018 in this cohort study. Cancer survivors with an AUD diagnosis during their index hospitalization were included in the exposure group. Propensity score matching was used to identify cancer survivors without AUD for the control group. The primary outcome was all-cause readmission, and secondary outcomes included days to, length of, and total cost of readmission. Outcomes were measured after 90 and 180 days of follow-up. Logistic regression was used to measure the likelihood of readmission, and negative binomial regression and gamma regression were used for the other outcomes. Results: Of 485,962 cancer survivors, 13,953 (2.9%) had co-occurring AUD. Cancer survivors with AUD had slightly higher odds of 90-day (odds ratio, 1.14; 95% CI, 1.06–1.22) and 180-day (odds ratio, 1.11; 95% CI, 1.05–1.18) readmission compared with those without AUD. Cancer survivors with AUD who were readmitted after 90 days also had higher readmission costs ($3,785 vs $3,376; P =.03). No differences in time to and length of readmission were observed between groups. The odds of readmission were higher among cancer survivors with AUD irrespective of age and type of cancer. Male, but not female, cancer survivors with AUD were more likely than those without AUD to be readmitted in both follow-up periods. Conclusions: This population-based cohort study of cancer survivors in the United States found that AUD is associated with higher 90- and 180-day readmission rates and higher related health care costs after 90 days of follow-up. Hospitalized cancer survivors with AUD may benefit from addiction treatment and discharge planning that addresses their co-occurring AUD.