tbuckley/cabot-search huggingface dataset:
TMOD-02. GEBTO: GENETICALLY ENGINEERED BRAIN TUMOR ORGANOIDS AS A NOVEL PRECLINICAL MODEL
Authors: Jens Bunt, Mieke Roosen, Evie Egelmeers, Joris Maas, Zelda Ode, Marcel Kool
Journal: Neuro-Oncology (2021)

Abstract Background One of the bottlenecks in basic and translational research on pediatric brain tumors, is the lack of suitable and representative preclinical models to study tumor biology and drug sensitivity. Over the last decades, extensive molecular characterization has uncovered many entities and subgroups with their unique oncodriving events. However, this heterogeneity is currently not reflected in the models available, especially not for in vitro models. Objectives We aim to generate genetically engineered brain tumor organoids (GEBTO) to represent the molecular variety of embryonal brain tumors and ependymomas. Method Human brain organoids derived from embryonic stem cells are generated to represent the region of tumor origin. To mimic oncodriving events, DNA plasmids are introduced via electroporation in the organoid cells to knockout tumor suppressor genes or overexpress oncogenes. Results Cerebellar and cerebral forebrain organoids were generated as the tissue of origin for medulloblastoma and supratentorial ependymoma (ST-EPN), respectively. Based on the detection of GFP protein encoded by DNA plasmids, the organoid cells can be manipulated within a wide developmental window, which corresponds with the presence of the proposed cells of origin. Different oncodrivers and combinations thereof are now being tested to see whether they result in ectopic growth in cerebral or cerebellar organoids. When successful, the GEBTOs are histologically and molecularly characterized using (single cell) transcriptomic and epigenomic analyses to see how well they resemble human tumors. Discussion Although further development is required, GEBTOs provide a novel avenue to model especially rare pediatric brain tumors, for which tissue and therefore patient-derived models are limited. It also allows for in-depth analyses of the potential cells of origin and the contribution of different mutations to tumor biology.
Comparison of clinicopathological features and outcomes in patients with primary leiomyosarcoma of bone and soft tissue.
Authors: Alan T. Blank, Charles Gusho, Steven Gitelis
Journal: Journal of Clinical Oncology (2021)

e23526 Background: Leiomyosarcoma is a rare malignancy that may occur in bone. This investigation described the characteristics and outcomes of primary leiomyosarcoma of bone (PLB) compared to soft tissue leiomyosarcoma (SLMS). Methods: This study was a retrospective review using the Surveillance, Epidemiology, and End Results (SEER) database from 1975 to 2016. Continuous and categorial variables were described, and Cox regression were used to identify factors of prognostic significance. Results: Seven thousand five-hundred two patients met inclusion criteria. Seventy-four (1%) were PLB and 7428 (99%) were SLMS. On multivariable analysis for high-grade SLMS radiation (neoadjuvant: HR, 0.56; 95% CI, 0.4-0.8; p = 0.003, and adjuvant: HR, 0.75; 95% CI, 0.6-0.9; p = 0.008) and surgery (procedure specific) improved DSS, while age (HR, 1.013; 95% CI, 1.0-1.1; p &lt; 0.001), tumor size greater than or equal to 5 cm (HR, 3.16; 95% CI, 2.3-4.2; p &lt; 0.001), abdomen/pelvis/trunk/thorax tumors (HR, 1.31; 95% CI, 1.1-1.6; p = 0.006), and distant metastases at presentation (HR, 2.6; 95% CI, 2.1-3.3; p &lt; 0.001) negatively influenced DSS. Conclusions: Radiation and surgery positively influence survival in high-grade SLMS while chemotherapy appears to have no benefit. Surgery alone appears to lower the mortality risk in PLB.
Alliance A071601: Phase II trial of BRAF/MEK inhibition in newly diagnosed papillary craniopharyngiomas.
Authors: Priscilla Kaliopi Brastianos, Erin Twohy, Susan Michelle Geyer, Elizabeth Robins Gerstner, Timothy J. Kaufmann, Michael Ruff, Daniela Annenelie Bota, David A. Reardon, Adam Louis Cohen, Macarena Ines De La Fuente, Glenn Jay Lesser, Jian Li Campian, Pankaj Agarwalla, Priya Kumthekar, Daniel P. Cahill, Helen Alice Shih, Paul D. Brown, Sandro Santagata, Frederick G. Barker, Evanthia Galanis
Journal: Journal of Clinical Oncology (2021)

2000 Background: Craniopharyngiomas, a rare brain tumor along the pituitary-hypothalamic axis, can cause significant clinical sequelae. Surgery and radiation, the only effective treatments, can cause significant morbidity. Genetic analysis of craniopharyngiomas revealed that 95% of papillary craniopharyngiomas (PCP) have BRAF V600E mutations (Brastianos et al. Nature Genetics 2014). We evaluated the efficacy of BRAF/MEK inhibition in patients (pts) with previously untreated PCP. Methods: Eligible pts without prior radiation whose PCP screened positively for BRAF mutations were treated with oral vemurafenib/cobimetinib in 28-day cycles. The primary endpoint of response rate (RR) based on centrally determined volumetric data was evaluated in 16 pts, where a partial response was defined as &gt;20% decrease in volume. This single arm, Simon two-stage phase 2 trial had 89% power to detect a true RR of at least 30% (vs. the null RR 5%; alpha=0.04). In this design, 3 or more observed volumetric responses in 16 evaluable pts would be considered promising activity. Results: In the 16 pts evaluated, 56% were female, and the median age was 49.5 years. Median follow-up was 22 months (95% CI: 16-26.5) and median number of treatment cycles was 8. Three patients progressed after therapy was discontinued and none have died. Based on volumetric response criteria, 14 of 15 pts with volumetric data available for central review had response to therapy (93%; 95% CI: 68% to 99.8%). Of 16 patients evaluable based on local review, 15 had response to therapy (93.75%; 95% CI: 70% to 99.8%). The median tumor reduction was -83% (range: -52% to -99%). The one nonresponder received 2 days of treatment before coming off therapy due to toxicity. Median progression-free survival was not reached. Grade 3 toxicities at least possibly related to treatment occurred in 12 pts (rash in 6 pts). Grade 4 toxicities were observed in two pts: hyperglycemia (n=1) and increased CPK (n=1). Three pts discontinued treatment for adverse events. Conclusions: Vemurafenib/cobimetinib resulted in an objective response in all pts who received 1 or more cycles of therapy. Our study indicates that BRAF/MEK inhibitors could be a powerful tool in the treatment of previously untreated PCP and warrants further evaluation in larger studies. A second arm of this study is enrolling pts with progressive PCP after prior radiotherapy. Support: U10CA180821, U10CA180882; U24CA196171, U10CA180868 (NRG); Genentech; https://acknowledgments.alliancefound.org. Clinical trial information: NCT03224767.
The prognostic value of the interferon-gamma (IFNγ) signature in patients with macroscopic stage III melanoma treated with and without adjuvant systemic therapy.
Authors: Judith M. Versluis, Stephanie Blankenstein, Petros Dimitriadis, Joyce Sanders, Willem Hoefakker, Annegien Broeks, Winan J. van Houdt, Yvonne M. Schrage, Michel W.J.M. Wouters, Alexander Christopher Jonathan Van Akkooi, Christian U. Blank
Journal: Journal of Clinical Oncology (2021)

9579 Background: Recently, trials have shown the benefit of adjuvant aPD-1 therapy in macroscopic stage III melanoma patients. This treatment has been incorporated in daily clinical practice, however, a substantial part of patients still does not benefit from this therapy, as they develop recurrences. The aim of this study is to evaluate the results of adjuvant aPD-1 therapy and the potency of the IFNγ signature as a prognostic or predictive marker, as it has proven to be predictive of response in neoadjuvant trials. Methods: Patients participating in an ongoing biobank study and naïve for systemic therapy were included, between 10-2017 and 06-2020, after complete resection of macroscopic stage III melanoma. Approval and reimbursement of adjuvant therapy in the Netherlands started in 12-2018, resulting in 2 cohorts of similar high risk patients: prior to availability of adjuvant aPD-1 (cohort A) and thereafter (cohort B). Data cut-off for clinical data was January 1 st 2021. Transcriptome sequencing was performed on samples of stage III melanoma by CeGaT GmbH, IFNγ signature was determined on these data with the median as cut-off. Clinical data were compared between cohort A and B as intention-to-treat population, including patients with a recurrence before adjuvant therapy start (n=10). Results: In total, 99 patients were included: 50 in cohort A and 49 in cohort B. Majority of included patients had thick primary melanomas (Breslow &gt;2mm in 59.6%) and stage IIIC/IIID disease (83.3%) according to AJCC 8th edition. At a median follow-up of 20.6 months (95% confidence interval [CI] 16.6-24.7), median recurrence-free survival (RFS) was 6.1 months (95%CI 3.9-8.4) versus 22.8 months (95%CI 8.7-36.9), significantly in favor of cohort B (p=0.011). Median overall survival (OS) was not reached in both patient groups, but was overall significantly different (p=0.040), favoring cohort B. RNA sequencing was performed in 25 patients who received adjuvant therapy and in 24 who did not, excluding patients with an early recurrence (&lt;12 weeks). In both treatment groups median (p=0.003) and 12-months RFS (p&lt;0.001) was significantly higher for IFNγ high patients, but both IFNγ low and high patients show higher RFS rates when receiving adjuvant aPD-1 therapy (Table). Conclusions: Our study confirms RFS and OS benefit of adjuvant aPD-1 for patients with macroscopic stage III melanoma. IFNγ has shown to be a prognostic marker in both patients who were and were not treated with adjuvant therapy, as both patients with IFNγ high and low signatures show benefit from adjuvant therapy.[Table: see text]
External validity of social psychological experiments is a concern, but these models are useful
Authors: Youri L. Mora, Olivier Klein, Christophe Leys, Annique Smeding
Journal: Behavioral and Brain Sciences (2022)

We agree that external validity of social psychological experiments is a concern, we disagree these models are useless. Experiments, reconsidered from a situated cognition perspective and non-linearly combined with other methods (qualitative and simulations) allow grasping decision dynamics beyond bias outcomes. Dynamic (vs. discrete) insights regarding these processes are key to understand missing forces and bias in real-world social groups.
Priority levels in cancer patients admitted to medical intensive care at a safety net hospital.
Authors: Raisa Epistola, Michael Olufemi Shodiya, Jordan Epistola, Dong Chang, James Jen-Chi Yeh
Journal: Journal of Clinical Oncology (2021)

e18599 Background: Admissions of cancer patients to intensive care units (ICU) are increasing with improved mortality. While ICU care can be lifesaving, its higher cost does not always result in reduced mortality. Moreover, timely goals of care (GOC) discussions correlate with less ICU use in those with certain cancers. We investigate if hospital mortality and disposition outcomes for cancer patients correlate to triage by ICU providers. Methods: This subgroup analysis of a prospective cohort of 808 patients admitted to the ICU from 1 July 2015- 15 June 2016 at an academic safety net hospital included 106 patients diagnosed with cancer. Medical records were reviewed by ICU physicians, who assigned priority ranks using Society of Critical Care Medicine guidelines: 1: critically ill, needing treatment/monitoring not provided outside of ICU, 2: not critically ill, but requiring close monitoring/potentially immediate intervention, 3: critically ill patients with reduced likelihood of recovery, 4: not appropriate for ICU, equivalent outcomes achieved with non-ICU care. We did a chart review for factors like prior therapy and documentation of GOC discussions. Statistical tests were conducted to examine if priority levels correlate with disposition, mortality, and length of stay (LOS). Results: χ 2 -tests revealed priority rank correlated with disposition after hospitalization (p&lt;.05) with group 3 having the highest proportion of deaths and lowest proportion of discharges home. It revealed that mortality rate differed by group (p&lt;.05) with logistic regression showing that priority 3 predicted increased mortality (p&lt;.05). ANCOVA indicated ICU LOS differed by priority group (p&lt;.05), with priority 3 averaging the longest LOS. While priority 3 had the most in-hospital GOC discussions, relatively few were documented pre-hospitalization. Conclusions: Overall, our patients were accurately triaged, with worse mortality and discharge outcomes among priority 3 and a dearth of pre-hospitalization GOC documentation for all groups. Our data show the importance of triaging patients and having early, frequent GOC discussions to minimize ICU admission given increasing demand and costs. GOC discussions are associated with less aggressive medical care near death and better patient quality of life. Thus, holding these talks with our sickest patients prior to potential ICU admission is an area to improve cost-effective high quality care.[Table: see text]
Prevalence of advance care planning in a resident run clinic in an underserved community.
Authors: Swetha Ann Alexander, Vinay Mathew Thomas, David Wu, Radhika Kulkarni, William Rabitaille
Journal: Journal of Clinical Oncology (2021)

e24067 Background: Advance Care Planning (ACP) ensures that patients receive care that is in line with their values and preferences. ACP is best done in the outpatient setting. Despite recognizing the importance of ACP, the rates of ACP completion continue to be low. We conducted a retrospective study to determine the rates of ACP in a resident run primary care clinic in Hartford, Connecticut, which serves the underserved community. We looked at patient characteristics to find correlation with ACP completion. We also aimed to determine the reasons which could decrease the completion of ACP. Methods: This was a retrospective chart review. Patients who met any of the inclusion criteria [i) Age&gt;65 ii) End stage renal disease on dialysis iii) Metastatic/Recurrent cancer iv) End stage heart failure v) COPD Gold stage D] and were seen in the primary care clinic from September 1, 2019 to December 31, 2019 were selected. Their charts were reviewed to see if ACP was documented during primary care visits over the past two years. The demographics of the patients were noted. Subsequently, a survey was distributed to residents to determine the possible causes of low rates of ACP discussion. Results: The characteristics of the 373 patients included in the study are shown in Table 1. Only 14 (3.8%) of the 373 had documentation of ACP during their primary care visits. The characteristics of the 14 patients in whom ACP was done are as follows: Sex- Female 9/14 (64%); Ethnicity- Hispanic 10/14 (71%), African American 4/14 (29%); Religious Affiliation- Christian 13/14 (93%), None 1/14 (7%); Married/Partner 2/14 (14%). Patient demographics including sex (p 0.6), religious beliefs (p 0.8), and marital status (p 0.6) did not show any correlation with the likelihood of ACP completion. Of the 31 residents who answered the survey, the most commonly listed barriers to ACP completion were the following: lack of time to conduct these discussions (94%), forgetting to conduct ACP discussions (48%), and lack of training (19%). All the residents believed that ACP discussion was beneficial to patients and medical providers. Conclusions: The rates of ACP planning in our clinic are much lower than the national average. African American and Hispanics, who make up the majority of our clinic population, traditionally have had low rates of ACP completion. This is an important issue that needs to be addressed. Advance care planning training should be also be strengthened during residency. [Table: see text]
Annals Consult Guys - Case of the Prolonged PT/INR and Spinal Surgery
Authors: Geno J. Merli, Howard H. Weitz
Journal: Annals of Internal Medicine (2021)

Web ExclusivesJune 2021Annals Consult Guys - Case of the Prolonged PT/INR and Spinal SurgeryFREEGeno J. Merli, MD, Howard H. Weitz, MDGeno J. Merli, MDThomas Jefferson University, Philadelphia, Pennsylvania (G.J.M., H.H.W.)Search for more papers by this author, Howard H. Weitz, MDThomas Jefferson University, Philadelphia, Pennsylvania (G.J.M., H.H.W.)Search for more papers by this authorAuthor, Article and Disclosure Informationhttps://doi.org/10.7326/W20-0022 CME/MOC SectionsSupplemental MaterialAboutVisual Abstract ToolsAdd to favoritesDownload CitationsTrack CitationsPermissions ShareFacebookTwitterLinkedInRedditEmail The Annals Consult guys untangle the case of mysteriously elevated prolonged PT/INR in a patient who is being evaluated before spinal surgery.For more videos from and information on Annals Consult Guys, visit go.annals.org/ConsultGuys. Comments0 CommentsSign In to Submit A Comment Author, Article and Disclosure InformationAffiliations: Thomas Jefferson University, Philadelphia, Pennsylvania (G.J.M., H.H.W.)Disclosures: Geno J. Merli, MD, and Howard H. Weitz, MD, report that they have no financial relationships or interests to disclose.Editors' Disclosures: Christine Laine, MD, MPH, Editor in Chief, reports that her spouse has stock options/holdings with Targeted Diagnostics and Therapeutics. Stephanie Chang, MD, MPH, Deputy Editor, reports employment with the Agency for Healthcare Research and Quality, travel compensation from the Guidelines International Network, and participation in the Patient-Centered Outcomes Research Institute methodology committee. Vineet Chopra, MD, MSc, Deputy Editor, reports grants received from the Agency for Healthcare Research and Quality and royalties from UpToDate and Oxford University Press. Deborah Cotton, MD, MPH, Deputy Editor, reports that she has no financial relationships or interests to disclose. Eliseo Guallar, MD, MPH, DrPH, Deputy Editor, Statistics, reports that he has no financial relationships or interests to disclose. Christina C. Wee, MD, MPH, Deputy Editor, reports employment with Beth Israel Deaconess Medical Center and consultancy with Boston Medical Center. Sankey V. Williams, MD, Deputy Editor, reports that he has no financial relationships or interests to disclose. Yu-Xiao Yang, MD, MSCE, Deputy Editor, reports employment with the Perelman School of Medicine, University of Pennsylvania, and consultancies with the U.S. Food and Drug Administration and the State of Colorado. PreviousarticleNextarticle Advertisement FiguresReferencesRelatedDetails Metrics June 2021Volume 174, Issue 6Page: CG1 ePublished: 15 June 2021 Issue Published: June 2021 CopyrightCopyright © 2021 by American College of Physicians. All Rights Reserved.Loading ...
Impact of the G8 score on the outcome of a cohort of elderly patients with solid or hematological malignancies.
Authors: Federica Biello, Alessia Mennitto, Abdurraouf Mahmoud, Francesca Platini, Daniela Ferrante, Riccardo Bruna, Andrea Patriarca, Maura Nicolosi, Eleonora Ferrara, Paola maria Maggiora, Alessia Rua, Clara Deambrogi, David James Pinato, Marco Krengli, Gianluca Gaidano, Alessandra Gennari
Journal: Journal of Clinical Oncology (2021)

12038 Background: Elderly cancer patients may have important benefits from innovative treatments. However, they are often barred from clinical trials because of highly selective eligibility criteria, or due to biased and subjective physician standpoints including reluctance to invite elderly patients and fear of excessive toxicity. Indeed, geriatric assessment has been increasingly recognized as predictive and prognostic instrument to detect frailty in older adults with cancer. In this perspective, the G8 score is a simple and reproducible instrument to identify elderly patients who should undergo full geriatric evaluation. The aim of our study was to evaluate the impact of frailty assessment by the G8 screening tool on the outcome of onco-hematological patients. Methods: Between January 2017 and December 2020 the G8 screening tool was administered to patients, aged &gt;65 years, referred to our center for solid and hematological malignancies. G8 score was assessed at the time of first access. The primary endpoint was overall survival. Multivariate analysis was performed according to G8 score, age, tumor type, stage and treatment. Results: In the observation period, 430 patients were screened for frailty by G8; median age was 77 years (65-92); of these, 331 (77%) had a G8 score &lt;14. Pts with solid tumors were 310 (72%), 175 (57%) of whom had metastatic diseases; 227 (73%) had a G8 score &lt;14. Pts with hematological malignancies were 120 (28%), 100 (83%) of whom had a G8 score &lt;14. Systemic therapy was administered to 336 patients (78%). At a median follow up of 7.2 months (range 1 to 52) 101 pts (24%) were dead. Median overall survival (mOS) was 27 months (1-52+).Patients with solid tumors, classified as frail by a G8 score &lt;14 had a 3-fold risk of death compared with those with G8 &gt; 14 (OR 3.26, CI 95 1.5-7.2, p = 0.003). Conversely, this increased risk was not observed in hematological malignancies (OR 1.4, CI 95 0.4-4.6, p = 0.57). By multivariate analysis, G8 score was associated with a worse prognosis only in patients with solid tumors. Conclusions: Our analysis suggest that elderly frail patients with solid tumors have a significantly increased risk of death as compared to elderly fit patients. Conversely, no impact of frailty, as assessed by a G8 score &lt; 14, was evident in elderly patients with hematological malignancies.