tbuckley/cabot-search huggingface dataset:
IMMU-11. CLINICAL UPDATES AND CORRELATIVE FINDINGS FROM THE FIRST PATIENT WITH DIPG TREATED WITH INTRACRANIAL CAR T CELLS
Authors: Nicholas Vitanza, Ashley Wilson, Juliane Gust, Wenjun Huang, Francisco Perez, Catherine Albert, Navin Pinto, Rebecca Gardner, Rimas Orentas, Michael Berens, Michael Jensen, Julie Park
Journal: Neuro-Oncology (2021)

Abstract We report preliminary data for the first subject with diffuse intrinsic pontine glioma (DIPG) treated with intracranial CAR T cells. BrainChild-03 (NCT04185038) is a phase 1 trial of repetitively-dosed locoregional B7-H3-specific CAR T cells for children with recurrent/refractory central nervous system (CNS) tumors or DIPG. DIPG patients enroll on Arm C, on which B7H3CARs are delivered into the ventricular system via a CNS reservoir catheter. This study does not use lymphodepletion. Primary endpoints are feasibility and safety, with second endpoints of disease response. This 18-year-old female (BrainChild-03 S005) with radiographically-classic DIPG and biopsy-confirmed H3 K27M mutation enrolled on Arm C after progression 552 days from diagnosis following focal radiation and temozolomide, irinotecan, and bevacizumab. Apheresis and manufacturing produced 4.2x109 second-generation B7H3CARs with a methotrexate-resistant human DHFR mutein (huDHFRFS; L22F,F31S) in a single transcript in combination with the B7-H3-specific CAR and EGFRt, each separated by a T2A linker, allowing methotrexate selection and enrichment. At time of submission, she has received 10 every-other-week outpatient infusions of 1x107 B7H3CARs (first dose on October 2, 2020). She has had no DLTs, but has experienced grade 2 fever and grade 2–3 headache peaking ~12–48 hours after each infusion. Following the 8th CAR T cell infusion, she experienced increased focal weakness and dysarthria at ~72 hours with resolution after 48 hours. She has not experienced cytokine release syndrome (CRS). She has stable disease 138 days post-initial CAR T cell infusion. Frequently collected correlative studies have detected viable B7H3CARs in the CSF post-infusion via flow cytometry. CSF cytokine analysis has revealed elevations of CXCL10, GM-CSF, and G-CSF following B7H3CAR infusions, without correlation in the serum. A second evaluable subject with DIPG has also received 4 locoregional doses of 1x107 B7H3CARs without a DLT. She also has stable disease and detectable viable B7H3CARs in the CSF.
Evaluation of the cytotoxic effect of recombinant hexameric FasL protein (MegaFasL) on cultured thoracic cancers with emphasis on malignant pleural mesothelioma.
Authors: Thai-Lan Tran, Annette Alleva, Marc Dupuis, Jean-Pierre Rosat, Dao Nguyen
Journal: Cancer Research (2007)

5144  Introduction. Direct targeting of apoptosis-inducing receptors using recombinant death ligands such as TRAIL or FasL has significant translational value as molecularly targeted therapeutics. Activation of Fas to induce apoptosis of cancer cells has been achieved by either agonistic antibodies or the recombinant FasL/enhancer complex, none of which is clinically applicable. In this study, we evaluated the anticancer property of MegaFasL (Apoxis, SA) in cultured thoracic cancer cells in vitro either alone or in combination with cytotoxic chemotherapeutic drugs.  Materials and Methods. Twelve Fas-positive cancer cells (2 lung cancer, 3 esophageal cancer and 7 malignant pleural mesothelioma) or primary human normal cells (umbilical endothelial cells and epithelial keratinocytes) were treated with MegaFasL or with recombinant soluble FasL/enhancer complex (sFasL) at 5 to 100 ng/ml x 48 hours). In combination therapy, cancer cells were either pre-treated with cisplatin (0.25 to 3 microg/ml x 24hrs), paclitaxel (25 to 100 nM) x 3hours or concurrently treated with histone deacetylase inhibitors Trichostatin A (50 to 1000 nM) or MS275 (2.5 to 10 microM) x 12 hours. Cell viability and apoptosis were determined by MTT and TUNEL-based ApoBrdU assays respectively. Experiments were performed in quadruplicates.  Results. 8/12 cultured cancer cells are intrinsically sensitive (defined as IC50  20-fold reduction of MegaFasL IC50 values. This is observed in both MegaFasL-sensitive and -resistant cells. While either chemotherapy alone or MegaFasL alone (10 or 25 ng/ml) mediates less than 30% cell death in representative MPM cells H513, H2052 or H211, >90% of cancer cells treated with drug combinations undergo apoptosis. More importantly, primary normal cells are refractory to combinations of MS275 (5 microM) + MegaFasL (10 ng/ml) or cisplatin (1 microg/ml) + MegaFasL that induce > 80% reduction of cell viability in multiple cancer cells.  Conclusion. The recombinant hexameric MegFasL induces significant cytotoxicity in cultured thoracic cancer cells in vitro and this process is profoundly enhanced by different classes of chemotherapeutic drugs. Combinations of chemotherapy + MegaFasL at low drug concentrations are selectively cytotoxic to cancer cells and not primary normal cells. In vivo evaluation of the antitumor effect of cisplatin + MegaFasL or MS275 + MegaFasL on subcutaneous MPM H513 tumors in nude mice are ongoing.
Efficacy of CDK4/6i in the visceral crisis setting: Result from a real-world database.
Authors: Shaheenah S. Dawood, Kaylen Brzozowski
Journal: Journal of Clinical Oncology (2021)

1047 Background: The combination of the CDK4/6 inhibitors(CDK4/6i) and endocrine therapy has improved overall survival(OS) in patients(pts) with either endocrine sensitive or resistant disease who are not in visceral crisis. The goal of this retrospective analysis of a real world database was to look at the efficacy of CDK4/6i among pts with hormone receptor positive (HR+ve)/HER2-ve metastatic breast cancer(MBC) who present with visceral crisis at diagnosis. Methods: For this analysis, we utilized a federated network of de-identified health data representing approximately 64 million patient lives available through the TriNetX Platform. We identified 5966 pts who had HR+ve/HER2-ve MBC diagnosed between 2015 and 2020. OS was computed using the Kaplan Meier product limit method. Propensity score matching was performed on all comparisons of survival. Visceral crisis was defined as either liver metastases with liver dysfunction, lymphangitis with dyspnea or the presence of pancytopenia. Results: 906(15%) pts received CDK4/6i. OS any time after treatment among pts who did and did not receive CDK4/6i was significantly different (p=0.0002) favoring the group receiving CDK4/6i, with median OS at 59.6 months and 46.2 months and 2-year OS at 71.6% and 61.4% respectively. Among pts who received CDK4/6i versus another treatment as first line therapy, OS was significantly different(HR 0.7, 95%CI 0.57 – 0.86, p&lt;0.0001), and median OS was 59.6 months and 41.5 months respectively. 336 pts with HR+ve mbc presented with visceral crisis at the time of diagnosis of whom 61(18%) received CDK4/6i therapy as first line therapy. Median OS among pts who did and did not have visceral crisis at diagnosis and received treatment was 8.1 months and 210 months respectively. OS any time after initial treatment was significantly different among pts with visceral crisis who did and did not receive CDK4/6i (p=0.01), with 2-year OS at 26.1% and 8.1% and median OS at 11 months and 6 months respectively Conclusions: The use of CDK4/6i in the presence of visceral crisis at diagnosis was associated with a 5 month improvement in OS compared to chemotherapy. Future clinical trials should explore the use of CDK4/6i in the setting of visceral crisis.
The correlation between BRCA status and surgical cytoreduction in high-grade serous ovarian carcinoma.
Authors: Rachel Soyoun Kim, Janet Malcolmson, Xuan Li, Marcus Bernardini, Liat Frida Hogen, Taymaa May
Journal: Journal of Clinical Oncology (2021)

5543 Background: High grade serous ovarian cancers (HGSC) with BRCA mutation are biologically unique, with distinct molecular and clinical behaviour from sporadic cases. It is unclear if these biological differences translate to favorable outcomes at the time of primary cytoreductive surgery (PCS). The aim of this study is to compare the amount of residual disease following PCS in BRCA-mutated (BRCAm) and wildtype (BRCAwt) HGSC, and to assess whether BRCA status is an independent predictor of residual disease. Methods: We conducted a retrospective analysis of patients with HGSC with known germline and somatic BRCA mutation status, treated with PCS from 2000 to 2017. We compared the cytoreduction outcomes between the BRCAm and the BRCAwt cohorts and built a predictive model to assess whether BRCA status was associated with amount of residual disease at the time of PCS. Results: Of 355 women, 144 harbored germline or somatic BRCA mutations (41%) and 211 were BRCAwt (59%). BRCAm women tended to be younger (54 vs. 59; p &lt; 0.001), but there were no differences between the two groups in stage, disease burden at presentation, surgical complexity score, length of surgery, or perioperative complications. The BRCAm group had a higher rate of complete cytoreduction to no residual disease (0mm) [75% vs. 54%], and a lower rate of optimal cytoreduction (1-9mm) [16% vs. 34%] or suboptimal cytoreduction (≥10mm) [9% vs. 12%] (p &lt; 0.001). In our predictive model, after accounting for length of surgery, CA-125 level, stage, disease scores and surgical complexity scores, BRCAm status was predictive of complete cytoreduction to 0mm residual disease (OR 4.78; 95% CI 2.32-9.85; p &lt; 0.001). Conclusions: BRCA status is predictive of complete cytoreduction at time of PCS in HGSC. Timely availability of BRCA testing is paramount as it may aid in the therapeutic decision making between PCS or neoadjuvant chemotherapy in women with newly diagnosed HGSC.
Considerations in Publishing a Psychiatric Randomized Clinical Trial With Kenyan Children
Authors: Dost Öngür
Journal: JAMA Psychiatry (2021)

Our website uses cookies to enhance your experience. By continuing to use our site, or clicking "Continue," you are agreeing to our Cookie Policy | Continue JAMA Psychiatry HomeNew OnlineCurrent IssueFor Authors Podcast Publications JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry (1919-1959) JN Learning / CMESubscribeJobsInstitutions / LibrariansReprints & Permissions Terms of Use | Privacy Policy | Accessibility Statement 2023 American Medical Association. All Rights Reserved Search All JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Forum Archive JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry Input Search Term Sign In Individual Sign In Sign inCreate an Account Access through your institution Sign In Purchase Options: Buy this article Rent this article Subscribe to the JAMA Psychiatry journal
Brain mechanisms underlying neuropsychiatric symptoms in Alzheimer’s disease: a systematic review of symptom-general and –specific lesion patterns
Authors: Yaojing Chen, Mingxi Dang, Zhanjun Zhang
Journal: Molecular Neurodegeneration (2021)

Abstract Neuropsychiatric symptoms (NPSs) are common in patients with Alzheimer’s disease (AD) and are associated with accelerated cognitive impairment and earlier deaths. This review aims to explore the neural pathogenesis of NPSs in AD and its association with the progression of AD. We first provide a literature overview on the onset times of NPSs. Different NPSs occur in different disease stages of AD, but most symptoms appear in the preclinical AD or mild cognitive impairment stage and develop progressively. Next, we describe symptom-general and -specific patterns of brain lesions. Generally, the anterior cingulate cortex is a commonly damaged region across all symptoms, and the prefrontal cortex, especially the orbitofrontal cortex, is also a critical region associated with most NPSs. In contrast, the anterior cingulate-subcortical circuit is specifically related to apathy in AD, the frontal-limbic circuit is related to depression, and the amygdala circuit is related to anxiety. Finally, we elucidate the associations between the NPSs and AD by combining the onset time with the neural basis of NPSs.
Spike D614G — A Candidate Vaccine Antigen Against Covid-19
Authors: Paul-Albert Koenig, Florian I. Schmidt
Journal: New England Journal of Medicine (2021)

SARS-CoV-2 Vaccine Design A recent study of the D614G variant spike protein of SARS-CoV-2 sheds light on a mechanism underlying the relatively increased infectivity of virions expressing it and has...
Real-world treatment patterns in stages IA-IIIB non-small cell lung cancer.
Authors: Jay M. Lee, Rongrong Wang, Ibrahim M. Abbass, Daniel Sheinson, Matthew Kent, Ann Johnson, Janet Lee
Journal: Journal of Clinical Oncology (2021)

e20528 Background: Given the rising number of immunotherapy or targeted therapy trials, a call for real-world treatment (Tx) data among resectable non-small cell lung cancer (NSCLC) patients is needed. We describe Tx patterns and timelines to Tx. Methods: Retrospective data were collected from the SEER Medicare database. Patient inclusion criteria: newly diagnosed NSCLC stages IA to IIIB between 2010 and 2015, ≥65 years of age, and continuously enrolled in Medicare Part A and B and no HMO enrollment for ≥7 months prior to diagnosis (Dx) date. A subset of patients with a follow-up of ≥12 months after Dx or ≥6 months after surgery were evaluated for Tx patterns. Results: Among 31,921 NSCLC patients identified, the mean (SD) age was 76 (7) years and 51% were female. AJCC (7 th edition) stages included IA (25%), IB (21%), II (8%), IIIA (17%), and IIIB (30%). Among the 6,559 (21%) patients identified with a solitary pulmonary nodule (SPN) prior to Dx, the median [IQR] time from SPN to Dx was 29 [13, 67] days. Among the 24,952 (78%) patients who received Tx, the median [IQR] time from Dx to Tx was 31 [14, 54] days. Among 19,304 patients included in the Tx pattern analysis, 63% did not undergo surgery. Among resected patients with lymph node metastasis, only 64% (stage II), 74% (stage IIIA), and 52% (stage IIIB) of patients received chemotherapy (CT) before or after surgery (Table). Median [IQR] time in days between Dx and neoadjuvant or adjuvant CT was 29 [14, 48] and 84 [56, 119], respectively. Median [IQR] time in days between Dx and surgery was longer for patients with neoadjuvant Tx (Table). Median [IQR] time between surgery to adjuvant CT was 46 [33, 63] days, with 59% of patients receiving their adjuvant CT ≥ 6 weeks after surgery and 33% of patients receiving their adjuvant CT ≥ 8 weeks after surgery. Conclusions: A significant proportion of lymph node positive stage II or III NSCLC patients did not receive perioperative systemic therapy despite standard of care guidelines. This finding suggests a patient population with unmet need notwithstanding recommendations for systemic therapy. [Table: see text]
The role of selective internal radiation therapy for liver metastases from pancreatic adenocarcinoma after progression on prior chemotherapy.
Authors: Jonathan O Hackett, Rebecca S Crothers, Emma Shaughnessy, Giuseppe Cardaci, Alaar Kaard, Andrew Peter Dean
Journal: Journal of Clinical Oncology (2021)

e16272 Background: Selective internal radiation therapy (SIRT) has established benefit for liver metastases in colorectal cancer. Very little data exists on the use of SIRT for liver dominant metastatic pancreatic cancer. A 2015 phase II trial by Gibbs et al suggested that SIRT at diagnosis may be beneficial in liver metastases in pancreatic cancer, particularly in those who have had a previous primary resection. Methods: In this single-institute retrospective audit we identified eleven patients who had liver predominant metastatic adenocarcinoma of the pancreas who received SIRT at any stage of their treatment. Data was analysed from our electronic patient databases. Results: 11 patients with adenocarcinoma of the pancreas, who had SIRT following progression on chemotherapy were identified. 3 had a primary surgical resection. All patients had received a minimum of one line of chemotherapy and had ECOG performance status of 2 or less. The median time from diagnosis to SIRT was 13 months (range 5-24 months). Patients received Yttrium-90 microspheres with a median activity of 2.1GBq with all eleven receiving concurrent infusional 5-FU 225mg/m 2 /day for 7 days prior and 14 days after. The median survival after SIRT therapy was 6 months (range 2-19 months). The median overall survival from diagnosis was 20 months (range 12-31 months). SIRT appeared safe and well-tolerated with no associated 30 day all-cause mortality. One patient developed radiation induced asymptomatic portal hypertension and liver cirrhosis. Conclusions: This is the first report of the use of SIRT with radiosensitising concurrent infusional 5FU for metastatic pancreatic cancer after failure of prior chemotherapy. We conclude that SIRT with concurrent infusional 5FU offers an additional treatment option for patients with liver dominant metastatic pancreatic cancer, who maintain a good PS who have progressed on prior lines of chemotherapy. This can provide a durable treatment response and requires further exploration.
Comparison of the Power of Procalcitonin and C-Reactive Protein to Differentiate between Different Etiologies of Febrile Neutropenia in Patients with Prolonged Profound Neutropenia
Authors: Anke Verlinden, Véronique De Vroey, Ella Roelant, Ann L. R. Van de Velde, Zwi Berneman, Wilfried Schroyens, Alain Gadisseur
Journal: Blood (2017)
Serum-based assay for adnexal mass risk of ovarian malignancy.
Authors: Daniel Ure, Rowan Bullock, Gary Altwerger, Elena Ratner, Lesley Northrop
Journal: Journal of Clinical Oncology (2021)

5551 Background: A Deep learning neural network was developed to assess ovarian cancer risk in women presenting with adnexal mass into risk categories. The algorithm shows potential to improve on the performance of CA-125 as the standard biomarker to monitor women as a clinical management metric to trace increased risk of malignancy. Methods: Serum specimens from an enriched biobank (N = 2688) were collected during previous clinical studies from women presenting with an adnexal mass at risk of ovarian cancer. Protein biomarker data from these specimens were used to develop a novel neural network for binary stratification of ovarian cancer risk assessment. These specimens were divided between training and testing data sets using 5-fold cross validation during training. A randomized, separate sample set was withheld from use in training and testing the algorithm for independent validation purposes. As algorithm inputs seven biomarkers are used in the network: cancer antigen 125, human epididymis protein, beta-2 microglobulin, apolipoprotein A-1, transferrin, transthyretin, and follicle stimulating hormone. In addition to these biomarkers, the patient’s age and menopausal status are used. Menopause was defined as the absence of menses for ≥12 months. The algorithm uses supervised learning with known histopathology diagnoses as the labels for training. The algorithm is a classification deep feedforward neural network. The neural network is regularized using node dropout to reduce overfitting. The final layer of the neural network has two nodes and uses the softmax function to assign a binary classification of low or high-risk of malignancy. Results: Algorithm performance metrics are also shown comparing predicted results from the algorithm to the known malignancy diagnoses. The performance metrics are also compared below to the standard of care biomarker test, cancer antigen 125 (CA125), reporting increased sensitivity by 26.1%, and failure to reject the null hypothesis of equivalent specificity. Conclusions: The algorithm detected 91% of malignancies in the independent validation data. This high sensitivity in malignancy detection paired with the failure to reject the null hypothesis of equivalent specificity (Pearson’s chi-squared test p-value of 0.281) and negative predictive value (NPV) suggest the algorithm could be used two-fold. First, surgical referral to gynecological oncologists for women classified in the high-risk cohort. The second as a goal with future clinical validation, is that women with a low risk of malignancy might be able to delay surgery and enter into a serial monitoring clinical management care pathway.[Table: see text]
Gene Conversion Facilitates the Adaptive Evolution of Self-Resistance in Highly Toxic Newts
Authors: Kerry L Gendreau, Angela D Hornsby, Michael T J Hague, Joel W McGlothlin
Journal: Molecular Biology and Evolution (2021)

Reconstructing the histories of complex adaptations and identifying the evolutionary mechanisms underlying their origins are two of the primary goals of evolutionary biology. Taricha newts, which contain high concentrations of the deadly toxin tetrodotoxin (TTX) as an antipredator defense, have evolved resistance to self-intoxication, which is a complex adaptation requiring changes in six paralogs of the voltage-gated sodium channel (Nav) gene family, the physiological target of TTX. Here, we reconstruct the origins of TTX self-resistance by sequencing the entire Nav gene family in newts and related salamanders. We show that moderate TTX resistance evolved early in the salamander lineage in three of the six Nav paralogs, preceding the proposed appearance of tetrodotoxic newts by ∼100 My. TTX-bearing newts possess additional unique substitutions across the entire Nav gene family that provide physiological TTX resistance. These substitutions coincide with signatures of positive selection and relaxed purifying selection, as well as gene conversion events, that together likely facilitated their evolution. We also identify a novel exon duplication within Nav1.4 encoding an expressed TTX-binding site. Two resistance-conferring changes within newts appear to have spread via nonallelic gene conversion: in one case, one codon was copied between paralogs, and in the second, multiple substitutions were homogenized between the duplicate exons of Nav1.4. Our results demonstrate that gene conversion can accelerate the coordinated evolution of gene families in response to a common selection pressure.
Digging mediastinal holes with vigour: a word of caution
Authors: Tijs K. Tournoy, Kurt G. Tournoy
Journal: European Respiratory Journal (2021)

Transbronchial mediastinal cryobiopsy has a superior diagnostic yield versus endobronchial ultrasonography. However, this is exclusively explained for diagnoses other than lung cancer. Uncertainties about safety hinder implementation in routine practice. <https://bit.ly/3wo9kkO>
Covid-19: How did the health secretary respond to Dominic Cummings’s allegations?
Authors: Gareth Iacobucci
Journal: BMJ (2021)

In a four hour session with MPs on 10 June, England's health secretary responded in detail to the serious allegations made against him and the government by Dominic Cummings, the prime minister's former chief aide. 1 -3 Cummings told the committee on 26 May that he believed that Hancock "should have been fired for at least 15 to 20 things, including lying to everybody on multiple occasions." On care homesThe allegation "Hancock told us in the cabinet room that people [in hospital] were going to be tested before they went back to care homes," said Cummings, referring to March 2020.He added, "We only subsequently found out that that hadn't happened.The government rhetoric was, 'We put a shield around care homes,' and it was complete nonsense.Quite the opposite of putting a shield around them, we sent people with covid back to care homes.