tbuckley/cabot-search huggingface dataset:
Interindividual Differences in Cortical Thickness and Their Genomic Underpinnings in Autism Spectrum Disorder
Authors: Christine Ecker, Charlotte M. Pretzsch, Anke Bletsch, Caroline Mann, Tim Schaefer, Sara Ambrosino, Julian Tillmann, Afsheen Yousaf, Andreas Chiocchetti, Michael V. Lombardo, Varun Warrier, Nico Bast, Carolin Moessnang, Sarah Baumeister, Flavio Dell’Acqua, Dorothea L. Floris, Mariam Zabihi, Andre Marquand, Freddy Cliquet, Claire Leblond, Clara Moreau, Nick Puts, Tobias Banaschewski, Emily J.H. Jones, Luke Mason, Sven Bölte, Andreas Meyer-Lindenberg, Antonio M. Persico, Sarah Durston, Simon Baron-Cohen, Will Spooren, Eva Loth, Christine M. Freitag, Tony Charman, Guillaume Dumas, Thomas Bourgeron, Christian F. Beckmann, Jan K. Buitelaar, Declan G.M. Murphy
Journal: American Journal of Psychiatry (2021)

Objective: Autism spectrum disorder (ASD) is accompanied by highly individualized neuroanatomical deviations that potentially map onto distinct genotypes and clinical phenotypes. This study aimed to link differences in brain anatomy to specific biological pathways to pave the way toward targeted therapeutic interventions. Methods: The authors examined neurodevelopmental differences in cortical thickness and their genomic underpinnings in a large and clinically diverse sample of 360 individuals with ASD and 279 typically developing control subjects (ages 6–30 years) within the EU-AIMS Longitudinal European Autism Project (LEAP). The authors also examined neurodevelopmental differences and their potential pathophysiological mechanisms between clinical ASD subgroups that differed in the severity and pattern of sensory features. Results: In addition to significant between-group differences in “core” ASD brain regions (i.e., fronto-temporal and cingulate regions), individuals with ASD manifested as neuroanatomical outliers within the neurotypical cortical thickness range in a wider neural system, which was enriched for genes known to be implicated in ASD on the genetic and/or transcriptomic level. Within these regions, the individuals’ total (i.e., accumulated) degree of neuroanatomical atypicality was significantly correlated with higher polygenic scores for ASD and other psychiatric conditions, and it scaled with measures of symptom severity. Differences in cortical thickness deviations were also associated with distinct sensory subgroups, especially in brain regions expressing genes involved in excitatory rather than inhibitory neurotransmission. Conclusions: The study findings corroborate the link between macroscopic differences in brain anatomy and the molecular mechanisms underpinning heterogeneity in ASD, and provide future targets for stratification and subtyping.
Thrombotic Thrombocytopenia after ChAdOx1 nCoV-19 Vaccination
Authors: Sabine Eichinger, Theodore E Warkentin, Andreas Greinacher
Journal: New England Journal of Medicine (2021)

Thrombotic Thrombocytopenia after ChAdOx1 nCoV-19 VaccinationTo the Editor: Greinacher et al. (April 9) 1 report on the development of platelet-activating antibodies against platelet factor 4 (PF4) after ChAdOx1 nCoV-19 vaccination in patients without previous exposure to heparin.These patients had clinical features that mimicked autoimmune heparininduced thrombocytopenia.In serum samples obtained from these patients, platelets were shown to be activated in the absence of heparin.Platelet activation was shown to be inhibited when high doses of heparin were added to the serum samples.Thrombocytopenia after the administration of adenoviral gene transfer vectors has been reported.Platelet activation with the formation of adenovirus-platelet-leukocyte complexes leading to accelerated platelet clearance in the liver and thrombocytopenia is common after adenovirus administration.P-selectin and von Willebrand factor are critically involved in a complex interplay between platelets, leukocytes, and endothelium in mediating accelerated platelet clearance. 2,3hese adenovirus-platelet-leukocyte complexes are then taken up by the liver through interaction with membrane-associated heparan sulfate proteoglycans, which act as receptors for viral entry. 4 Heparin can lead to dose-dependent inhibition of this interaction. 5Perhaps the interaction with heparan sulfate may sensitize the body to the development of platelet-activating antibodies against PF4 and lead to heparin-induced thrombocytopenia and thrombosis.
Impact of G-CSF during neoadjuvant therapy on outcomes of operable pancreatic cancer.
Authors: Pranav Murthy, Mazen S Zenati, Samer S. AlMasri, Aatur D. Singhi, Annissa DeSilva, Alessandro Paniccia, Kenneth K. Lee, Richard L. Simmons, Nathan Bahary, Michael T. Lotze, Amer H. Zureikat
Journal: Journal of Clinical Oncology (2021)

4126 Background: Pancreatic ductal adenocarcinoma (PDAC) is an aggressive disease characterized by chronic inflammation and a tolerogenic immune response. Neutropenia is a common side effect of cytotoxic chemotherapy, managed with administration of recombinant granulocyte-colony stimulating factor (G-CSF, Filgrastim). The interleukin 17 – G-CSF – neutrophil extracellular trap (NET) axis promotes oncogenesis and progression of PDAC, inhibiting adaptive immunity. We evaluated the impact of G-CSF administration during neoadjuvant therapy (NAT) on oncologic outcomes in patients with operable pancreatic cancer. Methods: A retrospective review of all patients with localized PDAC treated with NAT prior to pancreatic resection between 2014 – 2020 was completed at a single institution. G-CSF administration, type, and dose were collected from inpatient and outpatient medical records. Results: Of 351 patients treated, 138 (39%) received G-CSF during NAT with a median follow-up of 45.8 months. Patients who received G-CSF were younger (64.0 vs 66.7, p = 0.008), had lower BMI (26.5 vs 27.9, p = 0.021), and were more likely to receive 5-FU based chemotherapy (42% vs 28.2%, p &lt; 0.0001), NAT dose reduction (40.6% vs 25.4%, p = 0.003), or experience febrile neutropenia (8.7% vs 3.3%, p = 0.029). No differences were observed in baseline or pathologic tumor staging. In patients who received G-CSF, 130 (94%) received Pegfilgrastim with a median cumulative dose of 12 mg (IQR 6-12). Patients who received G-CSF were more likely to have an elevated post-NAT neutrophil to lymphocyte ratio (45% vs 29.6%, p = 0.004) and systemic immune-inflammation index (39.5% vs 29.6%, p = 0.061). Receiving G-CSF was an independent predictor of perineural invasion (HR 2.4, 95 CI [1.08, 5.5], p = 0.031) and margin positive resection (HR 1.69, 95 CI [1.01, 2.83], p = 0.043). Patients who received G-CSF had decreased overall survival compared to patients who did not receive G-CSF (median OS: 29.2 vs 38.7 months, p = 0.0001). Receiving G-CSF during NAT was an independent negative predictor of progression free (HR 1.38, 95 CI [1.04, 1.83], p = 0.022) and overall survival (HR 2.02, 95 CI [1.45, 2.79], p &lt; 0.0001). In a subset of patients with available pre- and post-NAT serum specimens (n = 28), G-CSF administration resulted in an increased number of citrullinated histone H3 complexes following NAT (+1378±1502 vs -300.7±1147 pg/ml, p = 0.007), indicative of enhanced peripheral NET formation. Conclusions: In patients with localized PDAC receiving NAT prior to surgical extirpation, G-CSF administration is associated with worse oncologic outcomes and should be administered with caution. Prospective randomized as well as confirmatory clinical studies are in order.
Interpreting and addressing suboptimal immune responses after COVID-19 vaccination in solid organ transplant recipients
Authors: Peter G. Stock, Timothy J. Henrich, Dorry L. Segev, William A. Werbel
Journal: Journal of Clinical Investigation (2021)

Transplant recipients were excluded from the initial clinical trials determining safety and efficacy of the landmark COVID-19 vaccines. Further, there is increasing evidence that immunosuppressed transplant recipients have a blunted antibody response to COVID-19 vaccination. In a concerning report by Sattler et al. in this issue of the JCI, kidney transplant recipients not only lacked a humoral response following two doses of Pfizer BNT162b2, but also displayed substantial impairment of the cellular response to SARS-CoV-2 antigens. This Commentary addresses potential strategies for transplant providers to evaluate and augment vaccine immunogenicity given the likelihood that COVID-19 will remain a world-wide threat to the health of transplant recipients.
HGG-41. CHARACTERIZATION OF THE IMMUNE RESPONSE FOLLOWING VARIOUS RADIOTHERAPY TREATMENTS IN GLIOBLASTOMA
Authors: Carolina Cocito, Mylene Branchtein, Tatyana Gongora, Nadia Dahmane, Jeffrey Greenfield
Journal: Neuro-Oncology (2021)

Abstract Malignant gliomas represent 6.5% of all childhood brain neoplasms with a 5-years survival rate of less than 20%. Current standard of care for these tumors include radiotherapy; recent data in solid tumors indicate that adequate radiation protocols may synergize with immunotherapy strategies for better outcomes. Nonetheless, a great discrepancy between preclinical studies and clinical trials outcomes persists, the basis of which is not fully understood. One hypothesis may be due to different radiation protocols used. We used the GL261 syngeneic mouse model of glioma to test this hypothesis and characterize the immune response to radiotherapy, with either a single dose of 10Gy, a dose often used in preclinical models, or a fractionated treatment of 2Gy for five consecutive days (2Gyx5), as fractioned radiotherapy is most often used in patients. The immune content of the brain and the blood was assessed by flow cytometry in un-irradiated (control), 10Gyx1 and 2Gyx5 treated mice for three weeks after radiation. In the brain, both radiation regimens drastically reduced the number of CD45+ cells for the first two weeks after treatment. When compared to controls, 10Gyx1 but not 2Gyx5 treated mice showed a significant increase in tumor infiltrating lymphocytes (CD3+) starting from the second week following treatment. This effect persisted until three weeks post treatment. The 10Gyx1 dose was better tolerated by the resident microglia (CD45lowCD11b+) when compared to the 2Gyx5 treatment. Our data describe the dynamics through which the immune microenvironment responds to two radiation regimens over time. Our results show that 10Gyx1 is the most effective regimen to impede tumor growth and to induce lymphocyte infiltration once the system recovers from the treatment. Our work suggests that, in the GL261 model, the fractionated radiation treatment we tested may be less optimal in priming glioma cells to the immune system.
Palbociclib (P) in patients (pts) with head and neck cancer (HNC) with <i>CDKN2A</i> loss or mutation: Results from the Targeted Agent and Profiling Utilization Registry (TAPUR) study.
Authors: Evan P. Pisick, Michael Rothe, Pam K. Mangat, Liz Garrett-Mayer, Francis P. Worden, Jessica R. Bauman, Siqing Fu, Rom S. Leidner, Ani Sarkis Balmanoukian, Carmen Calfa, Daniel R. Carrizosa, Stacy D. D'Andre, Lisle Nabell, Min S. Park, Steven Francis Powell, Ramya Thota, Richard L. Schilsky
Journal: Journal of Clinical Oncology (2021)

6043 Background: TAPUR is a phase II basket study evaluating anti-tumor activity of commercially available targeted agents in pts with advanced cancers with genomic alterations. Results in a cohort of HNC pts with CDKN2A loss or mutation treated with P are reported. Methods: Eligible pts had advanced HNC, no standard treatment options, measurable disease, ECOG PS 0-2, and adequate organ function. Genomic testing was performed in CLIA-certified, CAP-accredited site selected labs. Pts received P at 125 mg orally once daily for 21 days, followed by 7 days off until disease progression. Pts matched to P had CDKN2A loss or mutation and no RB mutations. Simon 2-stage design tested the null disease control (DC) - defined as partial (PR), complete response (CR) or stable disease at 16+ weeks (SD 16+) - rate of 15% vs. 35% (power = 0.85; α = 0.10). If ≥2 of 10 pts in stage 1 have DC, 18 more pts are enrolled. If ≥7 of 28 pts have DC, the null DC rate is rejected. Secondary endpoints are progression-free survival (PFS), overall survival (OS) and safety. Results: 28 pts (64% male) with HNC with CDKN2A loss (20 pts) or mutation (8 pts) were enrolled from June 2016 to Sept 2019. All were eligible for efficacy and toxicity. Demographics and outcomes are summarized in Table. No objective response (OR) and 10 pts with SD16+ (9 with CDKN2A loss, 1 with mutation) were observed for a DC rate of 37% (95% CI: 21%, 50%); the null DC rate of 15% was rejected (p=0.005). 14 pts had at least one grade 3-5 adverse or serious adverse event (AE/SAE) at least possibly related to P with the most common being low WBC/platelets. Other grade 3-4 AEs included anemia, fatigue, hypocalcemia, and syncope. There was one pt with grade 5 respiratory failure likely due to extensive lung metastases and aspiration but P-related pneumonitis could not be ruled out. Conclusions: Monotherapy P demonstrated modest anti-tumor activity and clinically significant AEs in heavily pre-treated pts with HNC with CDKN2A loss or mutation. Additional study is warranted to confirm the efficacy of P in pts with HNC with CDKN2A loss or mutation. Clinical trial information: NCT02693535. [Table: see text]
YAP1 mutation as a novel predictor of response to anti-PD-1/PD-L1 treatment in pan-cancers.
Authors: Wei-guo Xu, Jing Zhu, Lin Li, Dongsheng Chen, Qin Zhang, Qianqian Duan, Si Li, Mingzhe Xiao
Journal: Journal of Clinical Oncology (2021)

2604 Background: YAP1 is the main downstream target of the Hippo pathway and acts as a transcriptional coactivator to regulate development processes. YAP1 amplification is a potentially useful biomarker for predicting treatment outcomes and identifying patients with a high risk of relapse who should be closely monitored in nonsurgical esophageal squamous cell carcinoma (ESCC). YAP1 overexpression has been identified in multiple solid cancers, which consistently correlated with unfavorable clinical outcomes. Previous work suggested that YAP1 alterations may enrich for responses to immune checkpoint inhibitors (ICI), validation of these findings in needed. Methods: Using 539-gene target-capture next generation sequencing, we analyzed the YAP1 mutation in 3547 tumor tissue or plasma ctDNA samples from different patients, and the public database of TACG was also compared. Data from MSK-IMPACT study (n = 1661, anti-PD-(L)1/CTLA-4 mono/ combined therapy) was retrieved and analysed. In survival analysis, Kaplan-Meier curves were compared by log-rank test, and the hazard ratio (HR) was determined through a multivariable Cox regression model. Results: In clinical cohort, the frequency of YAP1 mutation in 3547 tumor tissue or plasma ctDNA samples from different patients was 0.62 % (22 in 3547). Meanwhile, the frequency of YAP1 mutation in TCGA cohort was 0.90 % (99 in 10953). We further analyzed Kaplan-Meier curves from MSK-IMPACT study (n = 1661, anti-PD-(L)1/CTLA-4 mono/ combined therapy). In MSK-IMPACT cohort, mutation of YAP1 was associated with higher TMB (P = 0.022) and higher mutation count (P = 0.017) in pan-cancers. YAP1 mutation was associated with prolonged overall survival (OS) trend compared with YAP1 wt in pan-cancers (P = 0.15; HR, 2.209, 95% CI, 0.7109-6.8639). Conclusions: In our study, the frequency of YAP1 mutation was investigated in clinical and TCGA cohort, which might provide useful information to guide precision medicine. YAP1 mutation may serve as a novel predictor of response to anti-PD-1/PD-L1 treatment in pan-cancers via upregulating TMB and mutation count.
Progression-free survival (PFS) and second PFS (PFS2) by disease stage in patients (pts) with homologous recombination deficiency (HRD)-positive newly diagnosed advanced ovarian cancer receiving bevacizumab (bev) with olaparib/placebo maintenance in the phase III PAOLA-1/ENGOT-ov25 trial.
Authors: Patricia Pautier, Philipp Harter, Carmela Pisano, Claire Cropet, Susana Hernando Polo, Regina Berger, Takashi Matsumoto, Ignace Vergote, Nicoletta Colombo, Trine Jakobi Noettrup, Georges Garnier, Peter Hillemanns, Claudio Zamagni, Antonio Gonzalez Martin, Claudia Lefeuvre-Plesse, Dominik Denschlag, Alain Lortholary, Jalid Sehouli, Frederic Selle, Isabelle Laure Ray-Coquard
Journal: Journal of Clinical Oncology (2021)

5514 Background: In the Phase III PAOLA-1/ENGOT-ov25 trial (NCT02477644), the addition of maintenance olaparib to bev in pts with newly diagnosed advanced high-grade ovarian cancer (HGOC) resulted in a significant PFS benefit, particularly in HRD-positive (HRD+) pts (hazard ratio [HR] 0.33; 95% CI 0.25–0.45) (Ray-Coquard et al. NEJM 2019). We explored efficacy in HRD+ pts by disease stage. Methods: Pts with newly diagnosed, FIGO stage III–IV HGOC in response after platinum-based chemotherapy + bev received bev (15 mg/kg q3w for 15 months [mo]) + either olaparib (300 mg bid for 24 mo) or placebo (pbo). This exploratory analysis evaluated PFS (data cut-off [DCO]: Mar 22 2019) and PFS2 (DCO: Mar 22 2020) in HRD+ pts (tumor BRCA1/ BRCA2 mutation [tBRCAm] or genomic instability score [Myriad myChoice HRD Plus] ≥42) by FIGO stage. Results: 387/806 randomized pts (48%) were HRD+; 272/387 (70%) had stage III disease and 115/387 (30%) had stage IV disease. 153 (56%) HRD+ stage III pts and 61 (53%) HRD+ stage IV pts had a tBRCAm. Among HRD+ stage III pts, 172 (63%) had upfront surgery (51/172 [30%] had residual disease) and 90 (33%) had interval surgery (19/90 [21%] had residual disease); 52 (45%) HRD+ stage IV pts had upfront surgery (34/52 [65%] had residual disease) and 55 (48%) had interval surgery (18/55 [33%] had residual disease). Median follow-up for PFS and PFS2 was respectively 24.8 and 37.2 mo in HRD+ stage III pts and 24.0 and 37.0 mo in HRD+ stage IV pts. Median PFS, PFS2 and HRs are in the Table. Among HRD+ stage III pts, 36-mo PFS2 (olaparib + bev vs pbo + bev) was 74% vs 60%; among HRD+ stage IV pts, 53% vs 30%. Among HRD+ stage III pts with no residual disease after upfront surgery, HR (95% CI) for PFS was 0.15 (0.07–0.30) and for PFS2 was 0.22 (0.06–0.67). Among HRD+ stage III pts with residual disease after upfront surgery or who received neoadjuvant chemotherapy, or HRD+ stage IV pts, HR (95% CI) for PFS was 0.38 (0.27–0.53) and PFS2 was 0.68 (0.46–1.03). Conclusions: In the PAOLA-1 study, maintenance olaparib + bev provided a PFS and PFS2 benefit over pbo + bev in HRD+ pts, irrespective of FIGO stage and residual disease after upfront surgery. Clinical trial information: NCT02477644. [Table: see text]
Association of KMT2C mutations with favorable outcomes with immune checkpoint inhibitors across multiple tumor types.
Authors: Chunling Liu, Qianqian Duan, Qin Zhang
Journal: Journal of Clinical Oncology (2021)

2600 Background: The KMT2 (lysine methyltransferase) family of histone modifying proteins play important roles in regulating developmental pathways, and mutations in the genes encoding these proteins have been strongly linked to many solid tumor cancers. Recently, there is emerging evidence that KMT2 family genes are involved in sensitivity to immune checkpoint inhibitors (ICIs) by modulating the immune environment. Here we explored the relationship between KMT2C mutation and its efficacy of immunotherapy. Methods: 1661 patients with next-generation sequencing (NGS) and immunotherapy data obtained from MSKCC clinical cohort were used to explore the association with KMT2C mutation and TMB and efficacy of ICIs. TMB was defined as the total number of somatic nonsynonymous mutations in the coding region. NGS data of 6624 pan-cancer patients who also detected MSI and PD-L1 expression from the Chinese clinical dataset were also analyzed relevance of mutation and these immune-related indicators. Results: In total, 9.81% (163/1661) patients in MSKCC cohort harbored KMT2C mutation. In the Chinese cohort, the KMT2C mutation ratio (11.19%, 741/6624) was similar to MSKCC. The TMB level of KMT2C mutation group in both MSKCC cohort and Chinese pan-cancer patient cohort was significantly higher than wild-type group (P &lt; 0.001). A multivariable analysis across the pan-cancer cohort using Cox proportional-hazards regression demonstrated that KMT2C mutation was significantly associated with better OS (hazard ratio, 0.69; 95%CI, 0.52-0.90; P = 0.006), and association remained significant with bladder (P = 0.039), colorectal (P = 0.024), melanoma (P &lt; 0.001) and renal (P &lt; 0.001), adjusting for cancer age, sex, metastases or primary. In addition, in Chinese cohort, KMT2C mutation was associated with higher PD-L1 positive expression (≥1%) (P = 0.01203) and MSI-H (P &lt; 0.001). Conclusions: KMT2C mutation shows impressive association with efficacy of ICIs. Meanwhile, KMT2C-mutant group has a higher TMB, PD-L1 expression and MSI-H. These results indicated that KMT2C mutation may serve as a good potential biomarker of ICI benefit in patients with multiple cancer types.
Effect of Matching Therapists to Patients vs Assignment as Usual on Adult Psychotherapy Outcomes
Authors: Michael J. Constantino, James F. Boswell, Alice E. Coyne, Thomas P. Swales, David R. Kraus
Journal: JAMA Psychiatry (2021)

Psychotherapists possess strengths and weaknesses in treating different mental health problems, yet performance information is rarely harnessed in mental health care (MHC). To our knowledge, no prior studies have tested the causal efficacy of prospectively matching patients to therapists with empirically derived strengths in treating patients' specific concerns.To test the effect of measurement-based matching vs case assignment as usual (CAU) on psychotherapy outcomes.In this randomized clinical trial, adult outpatients were recruited between November 2017 and April 2019. Assessments occurred at baseline and repeatedly during treatment at 6 community MHC clinics in Cleveland, Ohio. To be eligible, patients had to make their own MHC decisions. Of 1329 individuals screened, 288 were randomized. Excluding those who withdrew or provided no assessments beyond baseline, 218 patients treated by 48 therapists were included in the primary modified intent-to-treat analyses.Therapist performance was assessed pretrial across 15 or more historical cases based on patients' pre-post reporting across 12 problem domains of the routinely administered Treatment Outcome Package (TOP). Therapists were classified in each domain as effective (on average, patients' symptoms reliably improved), neutral (on average, patients' symptoms neither reliably improved nor deteriorated), or ineffective (on average, patients' symptoms reliably deteriorated). Trial patients were randomly assigned to good-fitting therapists (matched group) or were assigned to therapists pragmatically (CAU group). There were multiple match levels, ranging from therapists being effective on the 3 most elevated domains reported by patients and not ineffective on any others (highest) to not effective on the most elevated domains reported by patients but also not ineffective on any domain (lowest). Therapists treated patients in the matched and CAU groups, and treatment was unmanipulated.General symptomatic and functional impairment across all TOP domains (average z scores relative to the general population mean; higher scores indicate greater impairment), global distress (Symptom Checklist-10; higher scores indicate greater distress), and domain-specific impairment on each individual's most elevated TOP-assessed problem.Of 218 patients, 147 (67.4%) were female, and 193 (88.5%) were White. The mean (SD) age was 33.9 (11.2) years. Multilevel modeling indicated a match effect on reductions in weekly general symptomatic and functional impairment (γ110 = -0.03; 95% CI, -0.05 to -0.01; d = 0.75), global distress (γ110 = -0.16; 95% CI, -0.30 to -0.02; d = 0.50), and domain-specific impairment (γ110 = -0.01; 95% CI -0.01 to -0.006; d = 0.60), with no adverse events.Matching patients with therapists based on therapists' performance strengths can improve MHC outcomes.ClinicalTrials.gov Identifier: NCT02990000.