tbuckley/cabot-search huggingface dataset:
Clinical value of Next Generation Sequencing in Chinese pediatric soft tissue sarcoma: A multicenter data.
Authors: Suying Lu, Feifei Sun, Xiuli Yuan, Junting Huang, Juan Wang, Haixia Guo, Zijun Zhen, Jia Zhu, Xiaofei Sun, Yi Que, Lian Zhang, Chen Wang, Dan Wang, Yizhuo Zhang
Journal: Journal of Clinical Oncology (2021)

e22005 Background: To uncover the genomic characteristics as well as to, within the scope of pediatric soft tissue sarcoma (psts), assess the clinical value of Next Generation Sequencing (NGS), we present the first report of genomic profiles in Chinese psts. Methods: Tumor tissue, as well as peripheral blood from 41 psts patients, were collected in Sun Yat-Sen University Cancer Center, Shenzhen Children's Hospital and Nanfang Hospital. Samples were sequenced in a CLIA/CAP-accredited laboratory with a targeted NGS panel (Onco PanScan plus; GenetronHealth.inc) consisted of all exons of 831 cancer-related genes and mRNA of 395 genes. Bioinformatics analysis was conducted using a build-in computational pipeline. Results: A total of 41 samples consisted of five major histology types including rhabdomyosarcoma (RMS) (n = 11), fibrosarcoma (n = 4), Ewing's sarcoma (n = 4), INI1-deficient mesenchymal tumor (n = 4), and other mesenchymal tumors (n = 18). All patients were with doubtful diagnosis,advanced, relapsed, or refractory sarcoma, of which 85% samples were from initial diagnoses. In totally, we identified 116 somatic aberrations and 4 pathogenic or likely pathogenic germline mutations, with a median tumor mutational burden of 0.47/Mb (0–6.57). Genomic analysis revealed frequent alterations in TP53 (10%), NTRK fusion (10%), PAX3/7 fusion (8%), and ARID1A (7%). ARID1A (18% vs. 0%) and TP53 (18% vs. 3%) mutations were found with higher frequency compared with pediatric RMS data in a previous study (Jack et al 2014). ARID1A mutation was only reported in a RMS case report (Cramer et al 2017). Furthermore, the mutation of ARID1A potentially match PARP inhibitors, which may provide more therapeutic options. In addition, NGS aided pathologic diagnosis in 63% (26/41) patients. The proportion of confirmed diagnosis, differential diagnosis, and the excluded diagnosis was 41.5%, 12.2%, and 9.7%, respectively. Druggable alterations were detected in 39% patients (Table). Four patients received the treatment recommended by genetic testing, three of them with NTRK fusion were recruited in a matched clinical trial could be evaluated and showed partial remission upon Larotrectinib. Conclusions: We discovered ARID1A mutations, which potentially sensitive to PARP-inhibition, were at a higher incidence in Chinese RMS. This study demonstrated the value of NGS test in guiding the clinical practice of psts in Chinese population. [Table: see text]
A Dissenter's Journey
Authors: W. Philip T. James
Journal: Annual Review of Nutrition (2021)

After I studied medicine, my career took an early and unusual course when I was offered a clinical research post in Jamaica dealing with childhood malnutrition, of which I knew nothing. My subsequent nutritional explorations allowed gastrointestinal and metabolic analyses to have an impact on several public health policies. The biggest challenges came from unexpected political demands: coping with poor school performers in the Caribbean; addressing UK public health initiatives in health education; breaking the siege of Sarajevo; developing a Food Standards Agency as a sudden need for Tony Blair as incoming prime minister; dealing with widespread bovine spongiform encephalopathy in Europe; and responding to a United Nations request to assess global malnutrition. This last task revealed the need for a lifelong approach to nutrition, which also encompassed pregnancy. But perhaps the biggest challenge was establishing the criteria for obesity assessment, management, and prevention for policy makers across the globe.
Alcohol misuse is associated with poor response to systemic therapies for psoriasis: findings from a prospective multicentre cohort study*
Authors: I.Y.K. Iskandar, M. Lunt, R.J. Thorneloe, L. Cordingley, C.E.M. Griffiths, D.M. Ashcroft
Journal: British Journal of Dermatology (2021)

Background Factors that might influence response to systemic treatment for moderate-to-severe psoriasis are varied, and generally, are poorly understood, aside from high bodyweight, suggesting that other unidentified factors may be relevant in determining response to treatment. The impact of alcohol misuse on treatment response has not been previously investigated. Objectives To investigate whether alcohol misuse is associated with poor response to treatment for psoriasis. Methods This was a prospective cohort study in which response to systemic therapies was assessed using the Psoriasis Area and Severity Index (PASI). The CAGE (Cut down, Annoyed, Guilty, Eye opener) questionnaire was used to screen for alcohol misuse. A multivariable factional polynomial linear regression model was used to examine factors associated with change in PASI between baseline and follow-up. Results The cohort comprised 266 patients (biologic cohort, n = 134; conventional systemic cohort, n = 132). For the entire cohort, the median (interquartile range) PASI improved from 13 (10·0–18·3) at baseline to 3 (1·0–7·5) during follow-up. A higher CAGE score [regression coefficient: 1·40, 95% confidence interval (CI) 0·04–2·77]; obesity (1·84, 95% CI 0·48–3·20); and receiving a conventional systemic rather than a biologic therapy (4·39, 95% CI 2·84–5·95) were significantly associated with poor response to treatment; whereas a higher baseline PASI (–0·83, 95% CI –0·92 to –0·74) was associated with a better response to treatment. Conclusions The poor response to therapy associated with alcohol misuse and obesity found in people with psoriasis calls for lifestyle behaviour change interventions and support as part of routine clinical care. Targeting interventions to prevent, detect and manage alcohol misuse among people with psoriasis is needed to minimize adverse health consequences and improve treatment response.
A Retrospective audit comparing the neutropenic complications in the Pre-COVID and COVID era from a tertiary care center.
Authors: Narayanankutty Warrier, Deepa Chandramohan, Dilip Harindran Vallathol, Prasanth V. Parameswaran, Sajeevan K. V., Sreedharan P. S.
Journal: Journal of Clinical Oncology (2021)

e18619 Background: The COVID era has shown a rise in Intensive Care Unit (ICU) admissions. This is mainly due to COVID related complications. On the contrary, the public around the world have become more aware about maintaining proper hygiene by wearing masks , using hand wash and keeping themselves clean. As an audit, we conducted a retrospective analysis comparing neutropenic complications during the pre COVID and COVID times at our tertiary care cancer hospital. Methods: We collected data of febrile neutropenia admissions in ICU from March to July 2019-Non Covid (NC) and March to July 2020-Covid (C). The data collection was done including data on nadir total WBC count, use of GCSF, positive cultures, type of malignancy and deaths. The statistical analysis was done using SPSS software version 22. Results: There were 15 patients in the NC dataset and 18 patients in the C dataset. The mean age of NC was 59 (SD-9.2) and that of C was 57. 3 (SD-14). The age and sex were comparable in both the groups. The number of solid organ malignancies constituted 5 (33.33%) in NC set and 8 (44.44%) in C set. The hematological malignancies constituted 10 in each of C and NC sets. Gram negative sepsis was seen in 26.67% and 22.22% in NC and C dataset respectively. There were 4 (26.67%) deaths in NC group and 5 (27.28%) C group. Growth factors were received by 9 (60%) patients in NC group and 15 (83.3%) patients in the C group (p=0.0005). There was no significant difference in the admission, complication and death rates in ICU when comparing the two groups. These results have been depicted in Table. Conclusions: Despite the precautions taken by community during the COVID times, we conclude that there was no significant difference in the neutropenic complications. It also suggests that most of the neutropenic infections are related to the person’s immunity rather than community transmission. The study limitation is that this is a single center study but further audits and prospective studies are warranted in this regard. Keywords - COVID, Non COVID, Neutropenia, Intensive Care Unit. [Table: see text]
Sex‐Specific Response to Combinations of Shear Stress and Substrate Stiffness by Endothelial Cells In Vitro
Authors: Bryan D. James, Josephine B. Allen
Journal: Advanced Healthcare Materials (2021)

By using a full factorial design of experiment, the combinatorial effects of biological sex, shear stress, and substrate stiffness on human umbilical vein endothelial cell (HUVEC) spreading and Yes-associated protein 1 (YAP1) activity are able to be efficiently evaluated. Within the range of shear stress (0.5-1.5 Pa) and substrate stiffness (10-100 kPa), male HUVECs are smaller than female HUVECs. Only with sufficient mechanical stimulation do they spread to a similar size. More importantly, YAP1 nuclear localization in female HUVECs is invariant to mechanical stimulation within the range of tested conditions whereas for male HUVECs it increases nonlinearly with increasing shear stress and substrate stiffness. The sex-specific response of HUVECs to combinations of shear stress and substrate stiffness reinforces the need to include sex as a biological variable and multiple mechanical stimuli in experiments, informs the design of precision biomaterials, and offers insight for understanding cardiovascular disease sexual dimorphisms. Moreover, here it is illustrated that different complex mechanical microenvironments can lead to sex-specific phenotypes and sex invariant phenotypes in cultured endothelial cells.
Immunoregulation related gene of <i>CSMD2</i> and RNA activity as potential predicter of 2-year survival in pancreatic cancer: A DNA and RNA sequencing analysis.
Authors: Jiafei Yan, Si Li, Wenjing Xi, Dongsheng Chen, Mingzhe Xiao
Journal: Journal of Clinical Oncology (2021)

e16212 Background: The 5-year survival rate of pancreatic cancer remains as low as 3%-15%. One of the key approaches to enrich current treatment options or improve effectiveness is new biomarker probing. We conducted DNA and RNA sequencing analysis to reveal potential biomarkers related to overall survival. Methods: Whole-exome sequencing, RNA sequencing and clinical data for 209 patients with pancreatic cancer were downloaded from TCGA. Clinical factors and mutational landscape (insertion/ deletion/ single nucleotide variant) were compared between group of OS2+ (OS longer than 2 years) and OS2- (OS longer than 2 years) with T test and Chi-square Test. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses were conducted with RNA sequencing data to clarify the functional differences between the two groups. Results: The rates of OS2+ for patients in stage of I/II/III/IV was 43% (9/21), 17.8% (27/152), 0% (0/4), 0% (0/5), respectively. 152 patients in stage II were included for further analysis. No difference of sex and age were found between group of OS2+ and OS2-. Tumor mutation burden was comparable between the two groups. Mutation landscape showed the two groups had the accordance of 50% in top 10 genes. Mutations of CSMD2(18.5% vs. 5.0% , P = 0.026), CMYA5(14.8% vs, 2.5% , P = 0.019) and KCNA6(14.8% vs, 3.3%, P = 0.034) were more frequent in OS2+ group. CSMD2 is thought to be involved in the control of complement cascade of the immune system, and its low expression was significantly associated with differentiation, lymphatic invasion, and tumor size in colorectal cancer. CMYA5 was predicted as novel oncogene in breast cancer with the tool of Moonlight, it may also participate tumor activity in pancreatic cancer. The role of KCNA6 in cancer cell activity is barely known yet. Evaluation of differentially expressed genes between the two groups detected difference in leukocyte differentiation and T cell activation (GO analysis) and MAPK signal pathway (KEGG panalysis), these immunoregulation and MAPK pathways may play critical roles in tumor development and progression and affect the prognosis of pancreatic cancer. Conclusions: Pancreatic cancer with 2-year survival presented significant different DNA and RNA alterations, in which CSMD2 and pathway of leukocyte differentiation and T cell activation are closely associated with immunoregulation. These might provide guidance for prognose management and development of new therapeutic targets. Further mechanistic insights and prospective validation studies are warranted.
Tuberculosis diagnostic accuracy of stool Xpert MTB/RIF and urine AlereLAM in vulnerable children
Authors: Patrick Orikiriza, Julianna Smith, Bob Ssekyanzi, Dan Nyehangane, Ivan Mugisha Taremwa, Esther Turyashemererwa, Onesmas Byamukama, Tobias Tusabe, Elisa Ardizzoni, Ben J. Marais, Eric Wobudeya, Elizabeth Kemigisha, Juliet Mwanga-Amumpaire, Dora Nampijja, Maryline Bonnet
Journal: European Respiratory Journal (2021)

<b>Modest sensitivity but high specificity and good feasibility support the use of stool Xpert MTB/RIF in young children at high risk of disseminated tuberculosis; however</b>, <b>urine AlereLAM showed poor specificity and has little applicability</b>https://bit.ly/3oMLNHU
HER2 in uterine serous carcinoma: Testing platforms and implications for targeted therapy.
Authors: Tenley Klc, Sharon Wu, Annelise M. Wilhite, Nathaniel L. Jones, Matthew A. Powell, Alexander Olawaiye, Fiona Simpkins, Eugenia Girda, Jubilee Brown, Allison Puechl, Rouba Ali-Fehmi, Ira Seth Winer, Thomas J Herzog, Wolfgang Michael Korn, Britt Kristina Erickson
Journal: Journal of Clinical Oncology (2021)

5580 Background: HER2 is an emerging prognostic and therapeutic target in uterine serous carcinoma (USC). Testing algorithms and platforms in breast and gastric cancers are well studied and validated, but optimal HER2 testing in uterine cancer is not yet established. We aimed to assess the concordance of chromogenic in situ hybridization (CISH), immunohistochemistry (IHC), and next generation sequencing (NGS) platforms to aid in the development of USC specific testing guidelines. We also evaluated the rate of downstream mutations that may affect response to HER2 directed therapy. Methods: A total of 2,192 USC tumors were analyzed using NGS (NextSeq, 592 Genes and WES, NovaSEQ), a subset of 1,423 tumors were also tested by IHC and CISH (Caris Life Sciences, Phoenix, AZ). HER2 positivity through IHC (4B5, Ventana) and CISH (INFORM DUAL HER2 ISH Assay, Ventana) was determined based on 2007 and 2018 ASCO/CAP HER2 breast cancer guidelines. PD-L1 expression was tested by IHC using SP142 (Spring Biosciences) (positive cut-off &gt;1%). Microsatellite instability (MSI) was tested by fragment analysis (FA), IHC and NGS. Tumor mutational burden (TMB) was measured by totaling somatic mutations per tumor (TMB-high cut-off &gt; 10 mutations per Mb). Statistical significance was determined using chi-square. Results: Rates of HER2 positivity were comparable using the 2018 and 2007 breast cancer guidelines (19.5% vs 17.5%; p=0.25). Based on 2018 guidelines, the concordance between IHC and CISH was 98.9%. Specifically, 229/1423 patients (16%) were IHC+/CISH+, 5 patients (0.4%) were IHC+/CISH- and 11 patients (0.8%) were IHC-/CISH+ (Table). Common pathway alterations in HER2+ USC include TP53, RTK RAS, PI3K, NOTCH, chromatin remodeling and cell cycle genes. Single gene alterations in HER2+ tumors that may implicate HER2 therapy resistance (based on pathway analyses in other tumor types) included PI3K (36%), KRAS (2.6%), and PTEN (2.1%). HER2+ tumors had low immunotherapy biomarker profiles (0.3% MSI-H, 0.8% TMB, 17.1% PD-L1). Conclusions: High concordance rates were observed between CISH and IHC. Ultimately these testing platforms need to be validated by response to HER2 targeted therapies in order to develop USC specific HER2 testing guidelines.[Table: see text]
NVG-111, a novel ROR1xCD3 bispecific antibody for non-Hodgkin lymphoma.
Authors: David Granger, Satyen Gohil, Alessandro Barbarulo, Annalisa Baccaro, Vincent Muczynski, Kerry Chester, Fiona Germaschewski, Toby Batten, Kathryn Brown, Sarah Cook, Kieran O'Donovan, Parag Jasani, Amit C. Nathwani, Peter Phillips
Journal: Journal of Clinical Oncology (2021)

7549 Background: Receptor tyrosine kinase-like Orphan Receptor 1 (ROR1) is a type I transmembrane protein is highly expressed on an array of haematological and solid tumours. NVG-111 is a humanised, tandem scFv ROR1xCD3 bispecific antibody previously shown to elicit potent killing of tumour cells in vitro and in vivo by engaging a membrane-proximal epitope in the Wnt5a-binding Frizzled domain of ROR1 and redirecting T cell activity. The in vitro potency and pharmacodynamic responses to NVG-111 were assessed to support progression to a first-in-human study. Methods: The potency of NVG-111 in vitro was determined by evaluating the concentration response for cytotoxicity, T cell activation, and cytokine release in co-cultured Jeko-1 and unstimulated human T cells. Comparative data were generated for the marketed CD19xCD3 bispecific antibody, blinatumomab. Potency data for NVG-111 were used together with allometric scaling from murine PK studies to inform planned clinical doses. Results: NVG-111 demonstrated T cell-dependent cytotoxicity, T cell activation and levels of cytokine release similar in potency to blinatumomab. Cytotoxic responses of both NVG-111 and blinatumomab were more potent than T cell activation and cytokine release. Dose response curves for NVG-111 showed a decrease in activity beyond the concentration of maximal response (ie “hook effect”). We hypothesise this is due to receptor saturation, inhibiting synapse formation. NVG-111 has progressed to a Phase 1/2 first-in-human study in patients with debulked, relapsed/refractory chronic lymphocytic leukemia (CLL) and mantle cell lymphoma (MCL), the drug given as add-on to ≥2nd line therapy with a Bruton’s tyrosine kinase inhibitor, or venetoclax. Phase 1 includes escalating doses of 0.3 to 360 µg/day via continuous infusion over 3 cycles (each 21 days on, 7 days off) to establish safety, PK, pharmacodynamics (PD) and recommended phase 2 dose (RP2D). Predicted exposure at 0.3 µg/day is ̃EC 20 for cytotoxicity in vitro and below the lowest EC 10 for cytokine release. PD biomarkers in the study include systemic cytokines. Phase 2 will study efficacy and safety of the RP2D in CLL and MCL, with primary endpoint complete response rate; other efficacy endpoints include minimal residual disease and progression free survival. Conclusions: NVG-111 shows potent T-cell mediated lymphoma cell cytotoxicity in vitro at concentrations well below those associated with extensive cytokine release. NVG-111 is in an ongoing Phase 1/2 study and may present a novel option for adoptive immunotherapy in patients with non-Hodgkin lymphoma and potentially other cancers. Clinical trial information: 2020-000820-20. [Table: see text]
Weekly osimertinib dosing to prevent <i>EGFR</i> mutant tumor cells destined to home mouse lungs.
Authors: Ashwin Butle, Asim Joshi, Vanita Noronha, Kumar Prabhash, Amit Dutt
Journal: Journal of Clinical Oncology (2021)

e20504 Background: The recent ADAURA trial concludes daily dosing of adjuvant osimertinib, a third-generation EGFR tyrosine kinase inhibitor (TKI), improves disease-free survival with stage IB/II/IIIA EGFR-mutated non-small cell lung cancerpatients in comparison to placebo. We have developed a preclinical orthotopic mouse model, using luciferase tagged lung adenocarcinoma cells harboring EGFR TKI sensitive exon 19 deletion, to model and extend trial implications comparing a weekly vs daily dosing outcome of osimertinib to a first-generation TKI- erlotinib. Methods: We present an assessment of the homing of PC9-luciferase cells to the lungs of mice injected through mouse tail vein. Thirty NOD-SCID mice were divided into five groups as follows: two groups each for daily and weekly treatment and one group for vehicle control. For all the mice in the respective groups, erlotinib (25 mg/kg) and osimertinib (15 mg/kg) was orally administered. Homing of cells in the lungs of mice was assessed by bioluminescence imaging regularly. Results: In the control group, 100% of the mice showed homing and retention of cells in the lungs of mice 18 days post-injection. In mice receiving erlotinib daily, homing of the cells in lungs was absent in all four mice, except in one mouse where emergence was observed after day eight post-injection. In the case of erlotinib weekly group, out of four only one mouse showed absence of homing of cells in the lungs of mice. Interestingly, 100% of the mice in both the groups receiving osimertinib daily or weekly showed complete absence of homing of cells in the lungs of mice from day 3 onwards post-injection (Table). The tumors observed in the lungs, when dissected at day 30, confirmed the colonization of the injected cells homing to the organ. Conclusions: Based on the complete absence of the homing of cells in lungs of osimertinib treated mice, in both weekly and daily regimens, adjuvant osimeritinib may represent a viable treatment option in delaying the onset of disease post resection of early stage tumors or among patients with pre-disposition to EGFR mutant lung cancers harboring germline EGFR mutations. In addition, low-dose once-a-week osimertinib could potentially have several advantages over daily dosing, including lower toxicity, affordability, ease of administration and delaying or preventing acquired resistance that remains to be explored. [Table: see text]