Citations

Abstract Background Central Nervous System Non-Germinomatous Germ Cell Tumors (CNS-NGGCT) are rare but curable tumors. Due to their rarity, patients with treatment failures remain a poorly characterized group with unfavorable outcomes. In this study, we sought to characterize patients with treatment failures in a large, prospectively treated cohort. Methods European and North American clinical trials for patients with CNS-NGGCT (SIOP-GCT-96, SFOP-TGM-TC 90/92, COG-ACNS0122, and COG-ACNS1123) were pooled for analysis. Additionally, patients included and treated in the UK and France national registries under strict protocol guidelines were included as an independent, non-overlapping cohort. Results A total of 118 patients experienced a treatment failure. Twenty-four patients had progressive disease during therapy, and additional 11 patients were diagnosed with growing teratoma syndrome (GTS). Patients with GTS are significantly younger and present with local failures and negative tumor markers. Eighty-three individuals experienced disease relapses after treatment ended. Patients’ metastatic relapses presented significantly earlier than local relapses and were associated with tumor marker elevation (OR: 4.39; P = .026). In our analysis, focal or whole-ventricular radiation therapy was not associated with an increased risk of metastatic relapses. Conclusions Herein, we present the largest pooled dataset of prospectively treated patients with relapsed CNS-NGGCT. Our study identified younger age and negative tumor markers to be characteristic of GTS. Additionally, we elucidated that metastatic relapses occur earlier than local relapses are associated with elevated tumor markers and are not associated with the field of radiation therapy. These findings are of utmost importance for the planning of future clinical trials and the implementation of surveillance strategies in these patients.

Abstract Background: Pancreatic ductal adenocarcinoma (PDAC) is an aggressive cancer with a dismal prognosis. Although combined treatment with gemcitabine and albumin-bound paclitaxel has improved the prognosis of PDAC, both intrinsic and acquired chemoresistance cloud the outcomes. Hence, there is an urgent need to explore new therapeutic targets and formulate innovative strategies for the more effective treatment of PDAC.Methods: We transduced pancreatic cancer cells with a protein kinase library, and transfected cells were selected by puromycin treatment, followed by continuous exposure to vehicle control or gemcitabine/paclitaxel chemotherapy for 21 days. Next-generation sequencing as well as MAGeCK-VISPR analysis were performed to the identify candidate genes. Finally, we used the CRISPR-Cas9 to knockout the target gene, confirming that it is a viable target for overcoming chemoresistance in vivo and in vitro.Results: We identified several cell cycle checkpoint kinases and DNA damage-related kinases as targets for overcoming chemoresistance. Among them, cyclin-dependent kinase 7 (CDK7) ranked highly in both screenings. We demonstrated that both gene knockout and pharmacological inhibition of CDK7 by THZ1 result in cell cycle arrest, apoptosis induction. Furthermore, THZ1 synergized with gemcitabine and paclitaxel in vitro and in vivo, resulting in enhanced antitumor effects.Conclusions: Our findings support the application of CRISPR-Cas9 screening in identifying novel therapeutic targets and provide new strategies for overcoming chemoresistance in pancreatic cancer.

AbstractBackgroundElevated systolic blood pressure (SBP) and diastolic blood pressure (DBP) are risk factors for white matter (WM) injury associated with cognitive decline and dementia. White matter hyperintensities (WMH) on MRI, markers of WM injury, increase with aging and are more common in women than in men after the age of 60. We examined SBP and DBP in relation to WMH volume and diffusion MRI measures of WM integrity in postmenopausal women.MethodWomen (n=144) with median age of 67 (range 58‐72) and of good cardiovascular health who were previously enrolled in the multi‐site randomized clinical trial, Kronos Early Estrogen Prevention Study (KEEPS), participated in the present observational KEEPS Continuation Study. SBP, DBP, and MRI data were collected approximately 9 years after the end of KEEPS menopausal hormones versus placebo 4‐year interventions. WM integrity was assessed with WMH volume measurements (log transformed) on structural MRI and with measures of WM microstructure on diffusion MRI. Multiple linear regression analyses, adjusted for age, were used to test for associations of SBP and DBP with MRI measures.ResultThe median SBP was 128 (range 86‐180) and DBP was 77 (range 47‐106). Higher SBP (r=0.332;p=0.015) and DBP (r=0.346;p=0.007) were associated with higher WMH volumes. Among the WM tracts, higher SBP was associated with lower fractional anisotropy (FA) in lateral orbitofrontal gyrus WM (r=0.198;p=0.039) and sagittal stratum (r=0.226;p=0.043), and higher DBP was associated with lower FA in the superior occipital gyrus WM (r=0.370;p=0.045). Higher SBP and DBP were associated with higher mean diffusivity (MD) in the external capsule [(r=0.311;p=0.007);(r=375;p<0.001)] and the fronto‐occipital fasciculus [(r=0.286;p=0.016); (r=0.303;p=0.008)]. Furthermore, higher DBP was associated with higher MD in the anterior corona radiata (r=0.233;p=0.039), internal capsule (r=0.303;p=0.042), and the middle (r=0.275; p=0.03) and superior frontal gyrus (r=0.269;p=0.03) WM.ConclusionElevated SBP and DBP measurements are associated with greater WM injury in postmenopausal women. In particular, the frontal lobe WM and its connecting tracts may be more vulnerable to elevation in SBP and DBP. Whether BP control reduces the risk for WM injury, a risk factor for dementia, in post‐menopausal women warrants study.

Abstract Differences by sex in lung cancer incidence and mortality have been reported which cannot be fully explained by sex differences in smoking behavior, implying existence of genetic and molecular basis for sex disparity in lung cancer development. However, the information about sex dimorphism in lung cancer risk is quite limited despite the great success in lung cancer association studies. By adopting a stringent two-stage analysis strategy, we performed a genome-wide gene–sex interaction analysis using genotypes from a lung cancer cohort including ~ 47 000 individuals with European ancestry. Three low-frequency variants (minor allele frequency &lt; 0.05), rs17662871 [odds ratio (OR) = 0.71, P = 4.29×10−8); rs79942605 (OR = 2.17, P = 2.81×10−8) and rs208908 (OR = 0.70, P = 4.54×10−8) were identified with different risk effect of lung cancer between men and women. Further expression quantitative trait loci and functional annotation analysis suggested rs208908 affects lung cancer risk through differential regulation of Coxsackie virus and adenovirus receptor gene expression in lung tissues between men and women. Our study is one of the first studies to provide novel insights about the genetic and molecular basis for sex disparity in lung cancer development.

AbstractBackgroundLogopenic progressive aphasia (LPA) and posterior cortical atrophy (PCA) have distinct patterns of hypometabolism and atrophy. However, these clinical syndromes overlap: visuospatial impairment has been documented in LPA and aphasia in PCA. Rey‐Osterrieth Complex Figure – Copy (Rey‐O Copy) performance is correlated with parietal‐occipital atrophy in LPA. We explore visuospatial impairment on the Rey‐O Copy in LPA and PCA with the Mayo Older Americans Normative Studies (MOANS; which uses Meyers & Meyers criteria) and the Boston Qualitative Scoring System (BQSS). We also examine the proportion of visuospatial impairment in LPA, an under‐appreciated phenomenon, compared to PCA wherein it is fundamental.MethodPatients with LPA (n=25) or PCA (n=23) were recruited by the Neurodegenerative Research Group. Patients underwent comprehensive neuropsychological testing (including Rey‐O Copy) at baseline visit. Cut‐offs of T‐score=40 (BQSS) or scaled score=7 (MOANS) were used based on normative data. Proportions of patients with low performance were examined across LPA and PCA groups. Individual logistic regressions and AUROC analyses were then conducted to quantify differences in visuospatial impairment in LPA and PCA with both scoring systems. Identical analyses were conducted using raw scores corrected for age and sex, to avoid confounds of adjustments in normative data.ResultLPA and PCA groups were comparable on age, sex, and disease duration (LPA Median = 2.7 years, IQR=1.9‐3.5; PCA Median = 3.6 years, IQR=1.5‐4.9); p=.823). Surprisingly, 52‐72% of LPA participants demonstrated impaired performance across scoring systems, relative to 96% of the PCA group identified by both scoring systems. Odds ratios (OR) for the Rey‐O Copy MOANS (OR = 1.59; p=.008) and BQSS Copy Presence and Accuracy index (CPA; OR = 1.13, p=.002) were significant, persisting for age‐ and sex‐ controlled raw scores, suggesting the odds of a PCA diagnosis increased with decrement on Rey‐O Copy. AUROC values ranged from 0.77 to 0.88 across these indices.ConclusionA substantial number of LPA participants showed visuospatial impairment, despite initial primary language complaints. Differentiation of diagnostic groups by the Rey‐O is likely underscored by relatively uniform, profound, visuospatial impairment in PCA with more variability in LPA. However, the degree of visuospatial impairment overlaps remarkably across diagnoses.

Abstract Introduction: The management of CLL patients historically utilized FD chemoimmunotherapy (CIT), including fludarabine, cyclophosphamide and rituximab (FCR), or bendamustine and rituximab (BR). That changed with the introduction of Bruton Tyrosine Kinase inhibitors (BTKi) as an option for oral targeted monotherapy delivered continuously until disease progression or intolerance. Recently, novel combinations that include a B-cell lymphoma 2 inhibitor (BCL2i), such as venetoclax, have been developed as FD therapy. In addition, though not FDA approved, MRD assessment is emerging as a potential tool to guide FD therapy. Understanding the patient and their caregiver perspectives on FD and MRD is critical to providing the best care. Methods: CLL Society developed a web-based survey instrument of multiple-choice questions to assess patient and caregiver awareness, understanding, and preferences with MRD and FD therapies, where FD referred to both time and MRD guided limited duration therapies. Patients and caregivers were invited to participate via message boards, CLL Society's website, email, and online communities. Results: A total of 607 (96%) self-identified US patients and 36 (5%) caregivers, who answered on behalf of patients in their care, completed the survey between 31/AUG/2020 and 31/JAN/2021. The mean patient age was 64 (range, 30-90) years, 54% were female, 169 patients (27%) treatment-naïve, 239 (38%) with one line of prior therapy, and 214 (34%) with two or more. Targeted agents (e.g., venetoclax, ibrutinib, acalabrutinib, idelalisib, and duvelisib) had been used by 401 (64%). FD use with some novel therapies was known of by 565 (90%) patients, while 588 (93%) knew some were used as continuous daily treatment until disease progression or intolerance. If effectiveness and side effects were assumed similar, 485 (77%) preferred FD, and 398 (63%) wanted that finite treatment to be guided by MRD status. Only 42 (7%) preferred continuous therapy until disease progression or intolerance. The chance for continued remission while off treatment was ranked as a very important potential benefit after stopping a FD therapy by 581 (92%) patients. When considering therapy, 589 (93%), 575 (91%), 447 (71%), 415 (66%), 302 (48%), and 288 (46%) rated having overall survival, having future therapeutic options, avoiding chemotherapy, the ability to reach undetectable (u)MRD, minimal lab and office visits, and FD therapy as very important, respectively (Fig. 1). Being tested for MRD at least once was reported by 215 (34%), while 327 (52%) had not been tested, and 88 (14%) were unsure. There were 562 (89%) who were somewhat or very familiar with the term MRD, while 450 (71%) were confident of understanding what MRD testing measures, and 446 (70%) understood its role in CLL. Only 225 (36%) stated they understood different testing methods. While self-rated understanding of the indications for MRD testing was relatively high, some wanted testing done when not clinically indicated, such as when there was persistent CLL by routine laboratory findings, or at the time of diagnosis (Fig. 2). Respondents were mixed in their stated understanding as to which therapies could result in uMRD, with 241 (38%), 197 (32%), and 195 (32%) not knowing if CIT, BCL2i, and BTKi, could lead to uMRD, respectively. Two hundred and sixty-five (42%), 84 (13%), and 57 (9%) believed it was possible for most on a BCL2i, BTKi, or CIT to achieve uMRD, respectively (Fig. 3). If patients had evidence of MRD at the end of treatment, 365 (58%) would request frequent monitoring but would make no immediate treatment decisions based on MRD status, 279 (44%) were unsure, and only 88 (14%) would want further treatment immediately. Conclusions: The results from this patient-based study reveal a high awareness of FD therapies and MRD testing, as well as a clear preference for FD among internet-active patients and caregivers. However, there are gaps in the knowledge base, thus significant educational opportunities. Limitations included the opt-in sample where the survey results may not be projectable to the total CLL population. Moreover, the survey was not designed to assess preferences if either FD or continuous therapy offered improved outcomes. Nonetheless, as the potential role of MRD and FD therapy grows in CLL it will be incumbent on clinicians to ensure patients are well informed and engaged to help them better share therapeutic decisions. Figure 1 Figure 1. Disclosures Koffman: AbbVie: Current equity holder in publicly-traded company; AstraZeneca: Current equity holder in publicly-traded company, Honoraria; Beigene: Current equity holder in publicly-traded company; Bristol Myer Squibb: Current equity holder in publicly-traded company, Honoraria; Gilead: Current equity holder in publicly-traded company; Johnson & Johnson: Current equity holder in publicly-traded company, Honoraria; Sunesis Pharmaceuticals: Current equity holder in publicly-traded company; TG Therapeutics: Current equity holder in publicly-traded company; Regeneron: Current equity holder in publicly-traded company; Miragen Therapeutics: Current equity holder in publicly-traded company; Novartis: Membership on an entity's Board of Directors or advisory committees; Portola Pharma: Current equity holder in publicly-traded company; MEI Pharma: Current equity holder in publicly-traded company; Merck: Current equity holder in publicly-traded company. Stewart: Johnson & Johnson: Current equity holder in publicly-traded company; Novartis: Current equity holder in publicly-traded company; Dr. Reddy's Laboratories Limited: Current equity holder in publicly-traded company; Adaptive Biotechnologies: Current equity holder in publicly-traded company; Pacific Biosciences: Current equity holder in publicly-traded company. Byrd: Novartis, Trillium, Astellas, AstraZeneca, Pharmacyclics, Syndax: Consultancy, Honoraria; Vincerx Pharmaceuticals: Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees; Newave: Membership on an entity's Board of Directors or advisory committees. Danilov: Bayer Oncology: Consultancy, Honoraria, Research Funding; Genentech: Consultancy, Honoraria, Research Funding; Takeda Oncology: Research Funding; Rigel Pharm: Honoraria; TG Therapeutics: Consultancy, Research Funding; Abbvie: Consultancy, Honoraria; Beigene: Consultancy, Honoraria; Pharmacyclics: Consultancy, Honoraria; Gilead Sciences: Research Funding; Bristol-Meyers-Squibb: Honoraria, Research Funding; SecuraBio: Research Funding; Astra Zeneca: Consultancy, Honoraria, Research Funding. Davids: BeiGene: Consultancy; Janssen: Consultancy; Ascentage Pharma: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Astra-Zeneca: Consultancy, Research Funding; Pharmacyclics: Consultancy, Research Funding; BMS: Consultancy, Research Funding; MEI Pharma: Consultancy, Research Funding; Genentech: Consultancy, Research Funding; Adaptive Biotechnologies: Consultancy; AbbVie: Consultancy; Surface Oncology: Research Funding; TG Therapeutics: Consultancy, Research Funding; Celgene: Consultancy; Verastem: Consultancy, Research Funding; Eli Lilly and Company: Consultancy; MEI Pharma: Consultancy; Merck: Consultancy; Research to Practice: Consultancy; Takeda: Consultancy. Furman: Beigene: Consultancy; Acerta/AstraZeneca: Consultancy; Janssen: Consultancy, Honoraria; Sunesis: Consultancy; Genentech: Consultancy; Incyte: Consultancy; Pharmacyclics: Consultancy; TG Therapeutics: Consultancy; Loxo Oncology: Consultancy; Sanofi: Consultancy; Morphosys: Consultancy; Verastem: Consultancy; X4 Pharmaceuticals: Consultancy; Oncotracker: Consultancy; Abbvie: Consultancy, Honoraria, Other: Expert testimony; AstraZeneca: Honoraria. Jain: Bristol Myers Squibb: Honoraria, Research Funding; Genentech: Honoraria, Research Funding; AstraZeneca: Honoraria, Research Funding; Fate Therapeutics: Research Funding; Beigene: Honoraria; AbbVie: Honoraria, Research Funding; Pfizer: Research Funding; TG Therapeutics: Honoraria; Cellectis: Honoraria, Research Funding; Precision Biosciences: Honoraria, Research Funding; ADC Therapeutics: Honoraria, Research Funding; Aprea Therapeutics: Research Funding; Adaptive Biotechnologies: Honoraria, Research Funding; Servier: Honoraria, Research Funding; Janssen: Honoraria; Incyte: Research Funding; Pharmacyclics: Research Funding. Kay: Oncotracker: Membership on an entity's Board of Directors or advisory committees; Genentech: Research Funding; Targeted Oncology: Membership on an entity's Board of Directors or advisory committees; Morpho-sys: Membership on an entity's Board of Directors or advisory committees; Acerta Pharma: Research Funding; MEI Pharma: Research Funding; Behring: Membership on an entity's Board of Directors or advisory committees; Pharmacyclics: Membership on an entity's Board of Directors or advisory committees, Research Funding; AstraZeneca: Membership on an entity's Board of Directors or advisory committees; Rigel: Membership on an entity's Board of Directors or advisory committees; Abbvie: Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees; Dava Oncology: Membership on an entity's Board of Directors or advisory committees; Tolero Pharmaceuticals: Research Funding; CytomX Therapeutics: Membership on an entity's Board of Directors or advisory committees; Bristol Meyer Squib: Membership on an entity's Board of Directors or advisory committees, Research Funding; Agios Pharm: Membership on an entity's Board of Directors or advisory committees; TG Therapeutics: Research Funding; Sunesis: Research Funding; Juno Therapeutics: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding. Lamanna: Juno Therapeutics, Inc.: Research Funding; BeiGene: Consultancy; AstraZeneca: Consultancy, Research Funding; AbbVie: Consultancy, Research Funding; MingSight Pharmaceuticals, Inc.: Research Funding; Genentech, Inc.: Consultancy, Research Funding; Gilead Sciences, Inc.: Consultancy; TG Therapeutics, Inc: Research Funding; Verastem Oncology: Research Funding; Celgene Corporation: Consultancy; Oncternal Therapeutics: Research Funding; Pharmacyclics: Consultancy; Janssen Pharmaceuticals, Inc.: Consultancy. Mato: MSKCC: Current Employment; Pharmacyclics LLC, an AbbVie Company: Consultancy, Research Funding; TG Therapeutics: Consultancy, Other: DSMB, Research Funding; Nurix: Research Funding; BeiGene: Consultancy, Research Funding; Janssen: Consultancy, Research Funding; LOXO: Consultancy, Research Funding; Genmab: Research Funding; AstraZeneca: Consultancy; Sunesis: Consultancy, Research Funding; DTRM BioPharma: Consultancy, Research Funding; Acerta/AstraZeneca: Consultancy, Research Funding; Johnson and Johnson: Consultancy, Research Funding; AbbVie: Consultancy, Research Funding; Adaptive Biotechnologies: Consultancy, Research Funding; Genentech: Consultancy, Research Funding. Ujjani: Adaptive Biotechnologies: Research Funding; Atara Bio: Consultancy; Janssen: Consultancy; Epizyme: Consultancy, Membership on an entity's Board of Directors or advisory committees; TG Therapeutics: Honoraria; Gilead: Honoraria; ACDT: Honoraria; Kite, a Gilead Company: Honoraria; Loxo: Research Funding; AstraZeneca: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; AbbVie: Consultancy, Research Funding; Pharmacyclics: Consultancy, Research Funding. Pagel: Kite, a Gilead Company: Consultancy; Incyte/MorphoSys: Consultancy; AstraZeneca: Consultancy; Actinium Pharmaceuticals: Consultancy; Gilead: Consultancy; Pharmacyclics/AbbVie: Consultancy; MEI Pharma: Consultancy; Epizyme: Consultancy; BeiGene: Consultancy.

Aim To provide a contemporary analysis of incidence trends of infective endocarditis (IE) with its changing epidemiology over the past two decades in Europe. Methods A systematic review was conducted at the Mayo Clinic, Rochester. Ovid EBM Reviews, Ovid Embase, Ovid Medline, Scopus and Web of Science were searched for studies published between 1 January 2000 and 30 November 2020. All studies were independently reviewed by four referees and those that included a population-based incidence of IE in patients, irrespective of age, in Europe were included. Least squares regression was used to estimate pooled temporal trends in IE incidence. Results Of 9138 articles screened, 18 studies were included in the review. Elderly men predominated in all studies. IE incidence increased 4.1% per year (95% CI 1.8% to 6.4%) in the pooled regression analysis of eight studies that included comprehensive and consistent trends data. When trends data were weighted according to population size of individual countries, an increase in yearly incidence of 0.27 cases per 100 000 people was observed. Staphylococci and streptococci were the most common pathogens identified. The rate of surgical intervention ranged from 10.2% to 60.0%, and the rate of inpatient mortality ranged from 14.3% to 17.5%. In six studies that examined the rate of injection drug use, five of them reported a rate of less than 10%. Conclusion Based on findings from our systematic review, IE incidence in Europe has doubled over the past two decades in Europe. Multiple factors are likely responsible for this striking increase. Trial registeration number CRD42020191196.