tbuckley/cabot-search huggingface dataset:
P16.06 Immunophenotyping of tumor-infiltrating T cells in primary CNS lymphoma
Authors: S Schliffke, C Maire, M Holz, C Bokemeyer, M Westphal, K Lamszus, M Mohme
Journal: Neuro-Oncology (2021)

Abstract BACKGROUND Primary CNS lymphoma represents a malignant disease with dismal prognosis. Standard of care is high dose chemotherapy and radiation. However, this combination cannot be applied to the elderly and fragile population. Immunotherapy holds great promise to be effective in these patients. This study therefore aims to explore the phenotype of tumor-infiltrating lymphocytes (TIL) in order to analyze the potential for immune checkpoint inhibition. MATERIAL AND METHODS We performed ex vivo multicolor flow-cytometry on surgical specimens of nine patients with intracerebral lymphoma, including seven with primary CNS lymphoma after isolation of TILs following standard protocols. Data was analyzed using a Fortessa LSR flow cytometer and Diva software. The study was approved by the local ethics committee (PV4904). RESULTS Our ex vivo phenotyping demonstrated a predominant infiltration of CD8+ T cells, which outnumber CD4+ T cells by a ratio of 2:1 (p&amp;lt;0.01). Regulatory T cells (Tregs) were not increased in the tumor microenvironment and the NK cell frequency was reduced compared to the peripheral blood. While CD4+ T helper cells displayed significantly increased surface expression of multiple activation and checkpoint markers, including TIGIT, PD-1, Tim3 and CD57, cytotoxic CD8+ T cells predominantly expressed only TIGIT and PD-1. On average 70% and 80% of CD8+ T cells expressed PD-1 and TIGIT, respectively, compared to 35% and 60% of PD-1 and TIGIT on CD4+ T cells (p&amp;lt;0.05). CD8+ T cells furthermore showed an increased expression of CD39 and a simultaneous downregulation of CD73, both ectoenzyms involved in the modulation of intratumoral ATP, thereby indicating a metabolic immune modulation by the tumor. CONCLUSION Taken together, our study demonstrates a strong infiltration of cytotoxic CD8+ T cells into cerebral lymphoma, which potentially can be disinhibited using checkpoint immunotherapy. Our profiling suggests that PD-1 and TIGIT present appealing targets for such kind of immune disinhibition.
Long-term follow-up of ibrutinib monotherapy in treatment-naive patients with Waldenstrom macroglobulinemia
Authors: Jorge J. Castillo, Kirsten Meid, Joshua N. Gustine, Carly Leventoff, Timothy White, Catherine A. Flynn, Shayna Sarosiek, Maria G. Demos, Maria L. Guerrera, Amanda Kofides, Xia Liu, Manit Munshi, Nicholas Tsakmaklis, Lian Xu, Guang Yang, Andrew R. Branagan, Elizabeth O’Donnell, Noopur Raje, Andrew J. Yee, Christopher J. Patterson, Zachary R. Hunter, Steven P. Treon
Journal: Leukemia (2021)

Abstract Herein, we present the final report of a single-center, prospective phase II study evaluating ibrutinib 420 mg once daily in 30 treatment-naive patients with Waldenstrom macroglobulinemia (WM). The present study is registered with ClinicalTrials.Gov (NCT02604511). With a median follow-up of 50 months, the overall, major, and VGPR response rates were 100%, 87%, and 30%. The VGPR rate was numerically but not significantly lower in patients with than without CXCR4 mutations (14% vs. 44%; p = 0.09). The median time to a minor response was 0.9 months, and to a major response was 1.9 months, though were longer in those with mutated CXCR4 at 1.7 months ( p = 0.07) and 7.3 months ( p = 0.01). Six patients had disease progression. The median progression-free survival (PFS) was not reached, and the 4-year PFS rate was 76%. There was also a non-significant lower 4-year PFS rate in patients with than without CXCR4 mutations (59% vs. 92%; p = 0.06). The most common treatment-related adverse events were fatigue, upper respiratory infection, and hematoma. Atrial fibrillation occurred in 20% of patients. Ibrutinib monotherapy induced durable responses in treatment-naive patients with WM. CXCR4 mutations impacted VGPR attainment, time to major response, and 4-year PFS rate.
EXTH-12. INHIBITION OF EPIDERMAL GROWTH FACTOR RECEPTOR AND PLATELET-DERIVED GROWTH FACTOR RECEPTOR-ALPHA EXERTS SYNERGISTIC EFFICACY IN GLIOBLASTOMA
Authors: Evan Noch, Iyad Alnahhas, Laura Palma, Lewis Cantley
Journal: Neuro-Oncology (2021)

Abstract Epidermal growth factor receptor (EGFR) alterations, including amplification and activating mutations, occur in more than half of GBM cases. EGFR is located on Chr. 7, and Chr. 7 gain is one of the earliest events precipitating gliomagenesis. EGFR inhibitors, monoclonal antibodies, vaccines, and CAR-T cells have failed in GBM due to intrinsic heterogeneity and receptor tyrosine kinase (RTK) bypass pathways that mediate therapeutic resistance. New targeted therapeutic approaches to leverage synergistic combinations are desperately needed to improve GBM prognosis. Using the TCGA and other GBM databases, we previously demonstrated that PDGFRA amplification in patients with EGFR-amplified GBM carries significantly worse survival. EGFR and PDGFRA co-expression occur in more than one-third of GBM patients. The PDGFRA ligand PDGFA is also located on Chr. 7, and its expression is significantly increased with Chr. 7 gain and EGFR copy number increase. Therefore, Chr. 7 gain inherently leads to co-activation of both EGFR and PDGFRA signaling. We used patient-derived glioblastoma cells with Chr. 7 gain to test combined inhibition of EGFR and PDGFRA in vitro. We found that combined inhibition of both EGFR and PDGFRA using FDA-approved EGFR-targeted agents (Erlotinib, Gefitinib, Dacomitinib, Neratinib, and Osimertinib) and Crenolanib, respectively, leads to synergistic cytotoxicity in vitro. Inhibition of either EGFR or PDGFRA led to receptor cross-activation, and EGF and PDGF-AA-induced RTK activation was blocked by Neratinib and Crenolanib. Immunoprecipitation experiments and proximity ligation assays demonstrated that combined inhibition prevents EGFR and PDGFRA heterodimerization and pathways of therapeutic resistance. This combined inhibition led to decreased activation of downstream signaling pathways, including PI3K and MAPK. We show that combined inhibition of EGFR and PDGFRA exerts synergistic cytotoxicity in GBM and prevents resistance pathways that emerge during single-agent targeted therapy. These pathways are targetable with FDA-approved agents that could be used in patients with GBM with Chr. 7 gain.
Efficacy and safety of PXL770, a direct AMP kinase activator, for the treatment of non-alcoholic fatty liver disease (STAMP-NAFLD): a randomised, double-blind, placebo-controlled, phase 2a study
Authors: Kenneth Cusi, Naim Alkhouri, Stephen A Harrison, Pascale Fouqueray, David E Moller, Sophie Hallakou-Bozec, Sebastien Bolze, Jean-Marie Grouin, Sophie Jeannin Megnien, Julie Dubourg, Vlad Ratziu
Journal: The Lancet. Gastroenterology & hepatology (2021)
Abstract 3773: Impact of Chronic Statin Therapy on Arrhythmic Events in Patients With Acute Coronary Syndromes. The GRACE registry
Authors: Ameeth Vedre, Hitinder S Gurm, James B Froehlich, Eva Kline-Rogers, Gilles Montalescot, Joel M Gore, David Brieger, Rebecca Dedrick, Kim A Eagle
Journal: Circulation (2007)

Background: Animal studies have demonstrated a reduction in arrhythmias with the use of statins in models of myocardial ischemia. We hypothesized that chronic statin therapy might be associated with a reduction of in-hospital arrhythmic events in patients with acute coronary syndromes (ACS). Methods: We evaluated the in-hospital outcomes in 48,930 patients enrolled in the GRACE registry between 1999 and 2006 with an admission diagnosis of ACS. Patients were divided into two groups based on prior statin use. The primary outcome measure for this analysis was in-hospital occurrence of ventricular tachycardia (VT), ventricular fibrillation (VF) and atrial fibrillation (AF). Results: A total of 13,539 (28%) patients were on prior chronic statins and 35,391 (72%) were not. Those on chronic statins had higher rates of history of angina (69% vs 44%), diabetes (34% vs 22%), heart failure (15% vs 8%), hypertension (74% vs 58%), atrial fibrillation (9% vs 7%) and hyperlipidemia (84% vs 35%). They also had lower rates of in-hospital arrhythmias (Figure ). Chronic statin use remained strongly associated with a reduction in VT/VF (adjusted OR 0.61, 95% CI 0.54 – 0.69; P&lt;0.0001) and AF (adjusted OR 0.71, 95% CI 0.62– 0.80; P&lt;0.0001) in propensity-adjusted multivariable models. Conclusion: Patients on prior statins had a lower incidence of in-hospital arrhythmic events following ACS. It is not clear if the relationship is causal. Data from future randomized trials would need to definitively establish this association. Our study suggests another possible benefit from appropriate primary and secondary prevention therapy with statins.
Sixty seconds on . . . water fluoridation
Authors: Zosia Kmietowicz
Journal: BMJ (2021)

In a joint statement, the UK’s four chief medical officers have described tooth decay as “an entrenched inequality which needs to be tackled” and said that water fluoridation can help straighten it.1 Currently, around 6 million people in England live in areas with water fluoridation, mainly in the west Midlands and the North East.2

The Department of Health and Social Care say it’s a matter the medical chiefs have wanted to get their …
Doctors can decide if children are able to consent to puberty blockers, say judges
Authors: Clare Dyer
Journal: BMJ (2021)

It is for doctors to decide whether a child under 16 can give informed consent to treatment with puberty blockers, the Court of Appeal has ruled.1

Three senior judges, headed by the Lord Chief Justice, Lord Burnett, overturned a High Court decision which cast doubt on under 16s’ ability to understand the long term effects of puberty blockers and suggested court applications might be needed.

The Tavistock and Portman NHS Foundation Trust, which runs the UK’s only gender reassignment service for young people, appealed against the ruling. The High …
PL02.5.A The clinical significance of telomerase reverse transcriptase (TERT) promoter mutations, telomere length and O6-methylguanine DNA methyltransferase (MGMT) promoter methylation status in newly diagnosed and recurrent IDHwildtype glioblastoma (GBM) patients (PTS): A large mono-institutional study
Authors: G Lombardi, S Giunco, F Cavallin, C Angelini, M Caccese, G Cerretti, P De Bonis, A De Rossi, V Zagonel
Journal: Neuro-Oncology (2021)

Abstract BACKGROUND the clinical significance of TERT promoter mutations, telomere length and their interactions with MGMT promoter methylation status in patients with IDH-wildtype GBM patients remain unclear. We performed a large monoinstitutional study to better investigate their impact and their interaction on clinical outcomes MATERIAL AND METHODS TERT promoter mutations (C228T and C250T), relative telomere length (RTL) and MGMT methylation status were assessed in 278 newly diagnosed and in 65 recurrent IDH-wildtype GBM PTS which were treated at Veneto Institute of Oncology (Padua, Italy) from Dec 2016 to Jan 2020. We have retrospectively explored association between gene characteristics and neuroradiological response (RANO criteria), progression-free survival (PFS), overall survival (OS). Telomere length was measured by monochrome multiplex PCR and RTL values were calculated as a telomere/single-copy gene ratio RESULTS characteristics of newly diagnosed GBM PTS were: median age 63 ys, ECOG PS 0–1 in 71% of PTS, radical surgery in 38%, 78% received radiation therapy plus TMZ, MGMT was methylated in 53%, TERT promoter was mutated in 80% (75% C228T, 25% C250T), median RTL was 1.57 (range 0.4–11.37). Objective response rate was reported in 15% of PTS, median OS was 15ms (95% CI 13-18ms), median PFS was 8ms (95% CI 7-9ms). At multivariable analysis, TERT promoter mutations and RTL were not associated with clinical outcomes; about OS, TERT promoter mutations and RTL reported a HR of 1.05 (95% CI 0.64–1.64) and 0.99 (95% CI 0.89–1.10), respectively; MGMT methylated tumors showed significant improved PFS and OS with a HR of 0.54 (95% CI 0.40–0.71) and 0.47 (95% CI 0.34–0.64), respectively. All interactions among MGMT status, TERT mutation status and RTL were not statistically significant. Characteristics of recurrent GBM PTS were: median age 55 ys, ECOG PS 0–1 in 60% of PTS, MGMTmet in 37%, TERT promoter mutations in 75% (75% C228T, 25% C250T), RTL was 1.67 (range 0.68–8.87). At multivariable analysis, only MGMT methylated tumors resulted significantly associated to prolonged OS (HR 0.16; 95% CI 0.07–0.40). No gene interaction was significant CONCLUSION for the first time worldwide, we analyzed the impact of TERT promoter mutations, RTL and MGMT methylation status in both newly diagnosed and recurrent IDH-wildtype GBM PTS. TERT promoter status and RTL were not associated with clinical outcomes at both diagnosis and relapse. MGMT promoter methylation status was the only prognostic factor in both cases. No significant interaction was demonstrated between TERT promoter mutations, RTL and MGMT methylation status
NCCN Policy Summit: Innovative Solutions to Drive Down Healthcare Costs: Implications for Access to High-Quality Cancer Care
Authors: Terrell Johnson, Michelle McMurry-Heath, Ted Okon, David Rubin, Robert W. Carlson
Journal: Journal of the National Comprehensive Cancer Network (2021)

The cost of delivering high-quality healthcare in America now consumes 17.7% of the nation's gross domestic product according to Centers for Medicare & Medicaid Services National Health Expenditure Data. With costs threatening to disrupt accessible and equitable care for patients, policymakers are reassessing all matters and functions of the healthcare system to excise waste, redundancies, and costly services. To explore this subjects' impact on oncology, NCCN hosted the NCCN Policy Summit: Innovative Solutions to Drive Down Healthcare Costs: Implications for Access to High Quality Cancer Care. This virtual summit featured multidisciplinary panel discussions and keynote addresses. Seeking to address barriers to low-cost, high-quality cancer care, panelists and keynotes presented innovative policy solutions to sustain high-quality oncologic care at lower costs to the health system. This article encapsulates the discussions held during the summit and expounds upon salient points where appropriate.
Disaggregating Pacific Islanders and major Asian subpopulations to reveal hidden breast cancer disparities.
Authors: Kekoa Taparra, Edward Christopher Dee, Dyda Dao, Rohan Patel, Patricia Mae G. Santos, Fumiko Chino
Journal: Journal of Clinical Oncology (2021)

80 Background: The Asian American, Native Hawaiian, and Other Pacific Islander (AA/NHPI) population is the fastest growing and most socioeconomically heterogeneous racial/ethnic group in the US. AA/NHPI breast cancer outcomes are often reported as superior to Non-Hispanic Whites (NHW) however evidence suggests aggregating AA/NHPI masks disparities among subpopulations. As NHPI is often ignored as one of five official US races, this study aims to disaggregate AA and NHPI to unmask breast cancer disparities. Methods: An IRB exempt, retrospective cohort study using the National Cancer Database was conducted for women diagnosed with breast cancer in 2004-2016. AA and NHPI patients were compared with the majority NHW group. AA was separated into pertinent geographical origins: East Asian (EA; Chinese, Japanese, Korean), South Asian (SA; Indian, Pakistani), and Southeast Asian (SEA; Filipino, Vietnamese, Laotian, Hmong, Cambodian). Descriptive statistics were used. Logistic and Cox proportional hazard regressions assessed adjusted Odds Ratios (aORs) and adjusted Hazards Ratios (aHR), respectively, with 95% confidence intervals (95%CI). Analyses were adjusted for patient factors (age, insurance, income, rural/urban, education, hospital region, hospital distance, Deyo comorbidity score) and cancer characteristics (grade, stage, metastases, diagnosis year, hormone status). Results: Of 2,073,822 women there were 28,311 EA, 13,259 SA, 21,645 SEA, 5,375 NHPI, and 2,005,232 NHW. The median age was 62 years with median 66 month follow-up. Compared to NHW (9.6%), presentation with late-stage disease (Stage III/IV) was higher in NHPI (12%), SA (12%), and SEA (11%), but not EA (7.5%). On adjusted analysis (Table), EA was the only group with a statistical difference from NHW with aOR=0.85 (95%CI=0.76-0.94). Kaplan-Meier test for overall survival (OS) showed differences between ethnic/racial groups with NHPI having worse OS than AA subpopulations (p&lt;0.0001). On adjusted analysis (Table), all AA subpopulations had lower risk of death compared to NHW: EA (aHR=0.69; 95%CI=0.64-0.74), SA (aHR=0.65; 95CI=0.59-0.71), and SEA (aHR=0.78; 95%CI=0.73-0.84) however the NHPI group had a greater risk of death (aHR=1.14; 95%CI=1.02-1.28). Conclusions: NHPI women with breast cancer have worse outcomes compared to NHW. This is masked by superior AA outcomes when aggregated. The continual improper aggregation of AA with NHPI downplays NHPI cancer disparities. Proper disaggregation of NHPI from AA warrants greater attention.[Table: see text]
Bispecific antibodies targeting distinct regions of the spike protein potently neutralize SARS-CoV-2 variants of concern
Authors: Hyeseon Cho, Kristina Kay Gonzales-Wartz, Deli Huang, Meng Yuan, Mary Peterson, Janie Liang, Nathan Beutler, Jonathan L. Torres, Yu Cong, Elena Postnikova, Sandhya Bangaru, Chloe Adrienna Talana, Wei Shi, Eun Sung Yang, Yi Zhang, Kwanyee Leung, Lingshu Wang, Linghang Peng, Jeff Skinner, Shanping Li, Nicholas C. Wu, Hejun Liu, Cherrelle Dacon, Thomas Moyer, Melanie Cohen, Ming Zhao, Frances Eun-Hyung Lee, Rona S. Weinberg, Iyadh Douagi, Robin Gross, Connie Schmaljohn, Amarendra Pegu, John R. Mascola, Michael Holbrook, David Nemazee, Thomas F. Rogers, Andrew B. Ward, Ian A. Wilson, Peter D. Crompton, Joshua Tan
Journal: Science Translational Medicine (2021)

Bispecific antibodies targeting multiple regions of the SARS-CoV-2 spike protein comparably neutralize variants of concern and wild-type virus.
Utility of Liver Biopsy in Diagnosis and Management of High-grade Immune Checkpoint Inhibitor Hepatitis in Patients With Cancer
Authors: Michael Li, Jordan S. Sack, Phoenix Bell, Osama E. Rahma, Amitabh Srivastava, Shilpa Grover, Stephen D. Zucker
Journal: JAMA Oncology (2021)

The utility of liver biopsy in diagnosis
OS03.4.A Irradiation of the subventricular and subgranular zone and overall survival in high-grade glioma patients
Authors: D Bruil, S David, S Nagtegaal, J Verhoeff
Journal: Neuro-Oncology (2021)

Abstract BACKGROUND Previous research has shown that neural stem cells (NSCs) in the subventricular zone (SVZ) may support the growth of glioma by recruiting new cells to the tumor. NSCs are located in the SVZ as well as in the subgranular zone (SGZ) of the hippocampus, the two neurogenic niches of the brain. This might indicate that irradiation of the SVZ and SGZ, and thereby damaging NSCs, reduces tumor growth and improves overall survival (OS). However, irradiation may also inhibit the repair capacity of healthy brain tissue by these neurogenic niches. Therefore, we investigated the effects of SVZ and SGZ irradiation dose on OS, in a cohort of high-grade glioma patients. MATERIAL AND METHODS We have retrospectively selected 221 patients (2014–2020) with WHO grade III and IV gliomas that underwent radiotherapy. Next to clinical baseline characteristics, T1 weighted MRI- and CT-images were collected. The SVZ and SGZ regions on the individual T1 images were delineated via non-linear registration of brain atlases. SVZ labels were created in 0.5mm isotropic MNI T1 and T2 templates, while SGZ atlas labels were available via the Hippocampus and Subfields CoBrA atlas. Next, the mean dose from the acquired SVZ and SGZ labels were extracted. The relationship between SVZ doses, SGZ doses and OS were examined using the Cox proportional hazards model and the Kaplan-Meier method (using the Log Rank test for significance). RESULTS For the mean dose in the SVZ, the hazard ratio (HR) was 1.024 per Gy (P = 0.002, [95% confidence interval, 1.009–1.040]) and the mean SGZ dose had a HR of 1.021 per Gy (P&amp;lt; 0.001, [95% confidence interval, 1.012–1.031]). These results were then corrected for the following covariates: sex, age, total intracranial volume and extent of surgery. This resulted in a HR of 1.031 per Gy (P = 0,001, [95% confidence interval, 1.014–1.050]) for the mean SVZ dose, and a HR of 1.025 per Gy (P&amp;lt; 0.001, [95% confidence interval, 1.015–1.036]) for the mean SGZ dose. Patients whose SVZ received greater than the median SVZ dose (= 31.3 Gy) showed a significant decrease in OS compared to patients who received less than the median dose (10.7 months vs 13.5 months median OS, P = 0.001). Patients whose SGZ received greater than the median SGZ dose (= 31.9) showed a significant decrease in OS compared to patients who received less than the median dose (10.7 months vs 15.1 months median OS, P&amp;lt; 0.001). CONCLUSION Here, we present a large cohort of high-grade glioma patients, in which we show a statistically significant decrease in overall survival with increasing radiation dose on the SGZ and SVZ. This correlation suggests that both neurogenic niches might need to be spared during radiotherapy treatment to improve overall survival even in high-grade glioma patients. Modern radiotherapy planning and delivery options are available to implement this.
CONSOLIDATION OF FIRST REMISSION WITH 90Y-IBRITUMOMAB TIUXETAN IN ADVANCED FOLLICULAR NON-HODGKIN'S LYMPHOMA (FL): RESULTS FROM THE PHASE 3 RANDOMIZED FIRST-LINE INDOLENT TRIAL (FIT)
Authors: U. Vitolo, F. Morschhauser, J. A. Radford, A. Van Hoof, P. Soubeyran, H. Tilly, P. C. Huijgens, A. Kolstad, M. Kunz, A. Hagenbeek
Journal: Annals of Oncology (2008)
Diagnostics with modern genomics
Authors: Carlo Brugnara
Journal: American Journal of Hematology (2021)

In this special issue https://onlinelibrary.wiley.com/doi/toc/10.1111/(ISSN)1365-2141.modern.genomics.diagnostic.haematology, the American Journal of Hematology (AJH) has teamed up with other Wiley hematology journals (the British Journal of Haematology, European Journal of Haematology, Haemophilia and Hematological Oncology) to bring you a snapshot of the way next generation sequencing (NGS) is applied in the practice of hematology. Natural gene therapy by reverse mosaicism leads to improved hematology in Fanconi anemia patients Genetic screening of children with marrow failure. The role of primary immunodeficiencies Hematopoietic expression of a chimeric murine-human calreticulin (CALR) oncoprotein allows the assessment of anti-CALR antibody immunotherapies in vivo