tbuckley/cabot-search huggingface dataset:
Phase I trial of a novel epothilone, KOS-1584, using a weekly dosing schedule
Authors: A. Stopeck, E. Thomas, S. Jones, J. Cohen, G. Cropp, Y. Zhou, L. Feng, K. Kersey, A. L. Hannah, H. Burris
Journal: Journal of Clinical Oncology (2006)

2041 Background: Several epothilones are progressing through phase 1–3 clinical trials treating solid tumor malignancies. KOS-1584 is a 3rd generation epothilone with 3–12 fold increased potency compared to Epothilone D (as measured by in vitro cytotoxicity, in vivo xenografts or induction of G2/M arrest by flow cytometry) and improved pharmacologic/pharmacokinetic profile (enhanced tumor tissue penetration and reduced exposure to the CNS). This dose-escalation trial explores a weekly administration schedule of KOS-1584. Methods: Define the MTD, toxicity profile and PK of KOS-1584 when administered to patients with advanced solid malignancies via 1-hour infusion on Days 1, 8 and 15 every 4 weeks. Plasma PK and pharmacodynamics (serial sampling of PBMCs for soluble and polymerized microtubules by immunoblot) were assessed. Results: 12 pts (7 F; median age 60; median ECOG PS 1; median prior regimens 4, range 2–13) enrolled in 5 dose levels (0.8, 1.5, 2.5, 5.0 and 7.5 mg/m 2 ). To date, no Cycle 1 DLT has been seen; one Grade 3 episode of arthritis occurred in Cycle 2. Drug-related toxicities, all Grade 1 or 2 in severity: fatigue (n=3), anorexia (n=2) and individual patients with constipation, nausea, mucositis, dehydration, headache and pruritus. Neurotoxicity has not been observed. PK/parent (n=8): t½ 18.5 ± 6.8h, Vz 504 ± 234 L and CL 19.7 ± 6.1 L/h (none of these parameters showed evidence of dose dependency). 5.0 mg/m 2 Cmax 122.4 ± 60.6 ng/mL; AUCtot 688.2 ± 212 ng/mL*h. Dose proportional increase in exposure and Cmax was observed over the dose range tested to date. At 5.0 mg/m 2 the1-hr infusion Cmax is 3-fold higher and AUCtot 50% higher than for the same dose delivered over 3 hours. As predicted by allometric scaling from animals, Vz is ∼4-fold and t½ 2-fold higher than that of Epothilone D. Activity consisted of extended stable disease (a patient with colon cancer for 3 cycles). Dose-dependent increases in polymerized microtubules were observed: prior to infusion ∼10% of tubulin was in its polymerized form; this increased to 20%, 30%, 35% and 48% for the 1 st 4 dose levels at infusion end. Conclusions: Accrual is continuing in order to define the optimal dose on this regimen. Exposure and Cmax remain linear within this dose range; slower clearance is observed for the same dose administered over 1 hour compared to 3 hours. [Table: see text]
PL2.2 Pembrolizumab (PEM) in recurrent high-grade glioma (HGG)patients with mismatch repair deficiency (dMMR): an observational study
Authors: M Caccese, M Simonelli, M Fassan, M Padovan, P Persico, L Bellu, A Dipasquale, M Gardiman, S Indraccolo, V Zagonel, G Lombardi
Journal: Neuro-Oncology (2019)

Abstract BACKGROUND Pem, an immune checkpoint inhibitor, demonstrated to be activein various neoplasms with MMRd. No data exists about its efficacy in MMRdglioma patients. MATERIAL AND METHODS MMRd HGG relapsed after receiving RT and CT weretreated with Pem. MMR status was analyzed by immunohistochemistry,including the MLH1, MSH2, MSH6, and PMS2 markers. MMR deficiency wasdefined as presence of a weak (wMMRd) or absent (aMMRd) signal atimmunohistochemistry for at least one MMR protein. Other inclusion criteriawere: ECOG PS 0–2, histologically confirmed gliomas, dexamethasone ≤4 mg.Pem was administrated at 200 mg every 3 weeks until progression disease orunacceptable toxicity. Tumor response was evaluated by brain MRI every 10 weeksaccording to the RANO criteria. OS and PFS were evaluated by Kaplan-Meiercurves. CTCAE v4.0 was used for toxicity. RESULTS among 167 glioma patients, we found 22 MMRd gliomas. 12 PTS were treated with Pem: 8 wMMRd and 4 aMMRd. According to Bethesda criteria, allPTS had microsatellite stability. Tumor histologies included 5 anaplasticastrocytoma, 1 anaplastic oligodendroglioma, 6 glioblastoma (GBM). MSH2deficiency was found in 6 cases, MSH6 deficiency in 9 cases, PMS2 and MLH1deficiency in 2 cases. Median number of prior line of chemotherapy was 1 (range 1–5). Stable disease (SD) was reported in 4 PTS (33%); 8 PTS showedprogressive disease (PD). PTS with anaplastic gliomas showed a statisticallysignificant association with SD (p=0.03, OR=3); all GBM PTS reported PD; status of MMRd (weak/absent), IDH (mutated/wild-type), MSH2 and MLH6(deficient/proficient) were not associated with SD. Median follow up was 14.7 ms. OS was 5.6 ms (95% CI 0.1–13.8), PFS 2.4 ms (95% CI 1.8–2.9). OS was 2.8 ms and 5.6 ms (p=0.9), PFS was 1.8 ms and 3.1 ms (p=0.5) in PTS with wMMRd and aMMRd. PTS reporting SD and PD had PFS of 7.4 ms (95% CI 4.6–10.2) and 1.8 ms (95% CI 0.2–3.4), p=0.002; OS was “not reached” and 2.8 ms in PTS having SD vs PD (p=0.04). Grade ≥3 adverse eventswere reported in 8% of PTS. CONCLUSION a subgroup of recurrent MMRd HGG might benefit from Pem,especially anaplastic gliomas. There was a trend for a longer PFS and OS in PTS with aMMRd. Analyses for identifying additional molecular predictive factors is ongoing.
P10.06 Stiff limb syndrome associated to anti NMDA-R antibodies
Authors: C Birzu, L Jaume, S Rostomashvilli, J Honnorat, G Berzero, D Psimaras
Journal: Neuro-Oncology (2019)

Abstract BACKGROUND Stiff person spectrum disorder is a group of rare conditions clinically characterized by the core symptoms of fluctuating muscular stiffness with superimposed spasms and an exaggerated startle response (hyperkplexia). It includes multiple variants amongst which are focal forms like stiff limb syndrome. Up to date, it was described in association with a spectrum of antibodies interfering with gabaergic transmission, most frequently antibodies targeting GAD, glycine receptor, amphiphysin and more rare dipeptidylpeptidase like protein 6, gephyrin, GABAAR and Glycine transporter 2. MATERIAL AND METHODS We report the case of a stiff limb syndrome associated to anti-NMDAR antibodies. The patient, a French 44-year male, with no antecedents presents with a 2-month history of painful spasms in his both legs resulting in a difficulty of walking and multiple falls. The diagnosis was supported by a stiff limb syndrome clinical pattern, a clinical response to treatment with benzodiazepines and baclofen and by the absence of other neurological finding that could have suggested an alternative diagnosis. RESULTS Anti NMDA-R antibodies were identified in blood and CSF samples using both immunofluorescence and cell-based assay. Any other intracellular and surface antibodies were negatives, GAD-ab included. Oncological evaluation was negative. The patient didn’t present encephalopathy signs and neuropsychological evaluation was normal. The patient received immunotherapy with one cure of intravenous immunoglobulins after an only partial improvement with symptomatic treatment. CONCLUSION This is the first case report of an association between the anti NMDA-R and stiff limb syndrome. Further investigations are needed to provide a better understanding of the pathophysiology of stiff person spectrum disorders.
P11.26 Genome-wide shRNA screen identifies candidate genes driving glioblastoma invasion
Authors: A Schuster, V Neirinckx, E Klein, P V Nazarov, A Oudin, A Muller, F Azuaje, C Herold-Mende, B Klink, S P Niclou
Journal: Neuro-Oncology (2019)

Abstract BACKGROUND A major hallmark of glioblastoma (GBM) is its highly invasive capacity, contributing to its aggressive behaviour. Since invasive cells cannot be easily removed by surgery or irradiation, they are left behind and eventually result in lethal recurrence. Therefore, a better understanding of the invasion process and of the key molecular players underlying the invasive capacities of GBM may lead to the identification of new therapeutic targets for GBM patients. MATERIAL AND METHODS To identify candidate genes responsible for invasion, a genome-wide shRNA screen was performed in patient-derived GBM sphere cultures. The phenotype of the most promising candidate was validated in in vitro invasion assays, ex vivo brain slice cultures and in vivo orthotopic xenografts in mice. Gene knockdown in invasive GBM cell lines was compared with overexpression in non-invasive cells. RNA sequencing of knockdown cells, along with the generation of deletion constructs were applied to uncover the mechanisms regulating invasion. RESULTS Through a whole genome shRNA screen, a zinc-finger containing protein was identified as an invasion essential candidate gene. Knockdown of this gene confirmed a strong decrease in invasion capacity in two highly invasive GBM cell lines. In contrast, gene overexpression switched non-invasive GBM cells to an invasive phenotype. Deletion of either one or both zinc-finger motifs led to decreased invasion indicating that the two zinc-finger motifs are essential for regulating invasion. Mutation of the nuclear localisation signal resulted in retention of the protein in the cytoplasm and loss of the invasion phenotype demonstrating that the protein activity is required in the nucleus. Gene expression analyses revealed that invasion-related genes are significantly regulated by the candidate gene once it is localized in the nucleus. CONCLUSION We identified a zinc-finger containing protein as a novel driver of GBM invasion, presumably through a transcription factor activity resulting in the induction of an invasive transcriptional program. This protein and its downstream pathway may represent a novel promising target to overcome invasive capacities in GBM.
Exclusive: Government spending on management consultants trebles in three years
Authors: David Oliver
Journal: BMJ (2019)

The government’s spending on management consultants in the NHS has trebled during 2016-19 despite pledges by successive health secretaries to curb spending on external advisers.

The Department of Health and Social Care and its arm’s length bodies spent £22.65m on management consultants in 2018-19, up from £14.10m in 2017-18 and £6.53m in 2016-17, showed figures obtained under freedom of information. Non-departmental public bodies in these figures included the Care Quality Commission and NHS Improvement but not NHS England.

The increase occurred despite a target set by the former health secretary Jeremy Hunt in 2014 to save £10bn from the health budget by 2020 by cutting spending on management consultants, temporary agency staff, prescribing errors, and preventable harm, among other things.1

The findings on these central bodies are out of kilter with trends in the rest of the NHS. …
Trends in Racial/Ethnic Representation Among US Medical Students
Authors: Elle Lett, H. Moses Murdock, Whitney U. Orji, Jaya Aysola, Ronnie Sebro
Journal: JAMA Network Open (2019)

With increasing efforts to create a diverse physician workforce that is reflective of the demographic characteristics of the US population, it remains unclear whether progress has been made since 2009, when the Liaison Committee on Medical Education set forth new diversity accreditation guidelines.To examine demographic trends of medical school applicants and matriculants relative to the overall age-adjusted US population.Repeated cross-sectional study of Association of American Medical Colleges data on self-reported race/ethnicity and sex of medical school applicants and matriculants compared with population distribution of the medical school-aged population (20-34 years). Data from US allopathic medical school applicants and matriculants from 2002 to 2017 were analyzed.Trends were measured using the representation quotient, the ratio of the proportion of a racial/ethnic group in the medical student body to the general age-matched US population. Linear regression estimates were used to evaluate the trend over time for Asian, black, white, Hispanic, American Indian or Alaska Native (AIAN), and Native Hawaiian or Other Pacific Islander medical school matriculants by sex.The number of medical school applicants increased 53%, from 33 625 to 51 658, and the number of matriculants increased 29.3%, from 16 488 to 21 326, between 2002 and 2017. During that time, proportions of black, Hispanic, Asian, and Native Hawaiian or Other Pacific Islander male and female individuals aged 20 to 34 years in the United States increased, while proportions of white male and female individuals decreased and proportions of AIAN male and female individuals were stable. From 2002 to 2017, black, Hispanic, and AIAN applicants and matriculants of both sexes were underrepresented, with a significant trend toward decreased representation for black female applicants from 2002 to 2012 (representation quotient slope, -0.011; 95% CI, -0.015 to -0.007; P < .001).Black, Hispanic, and AIAN students remain underrepresented among medical school matriculants compared with the US population. This underrepresentation has not changed significantly since the institution of the Liaison Committee of Medical Education diversity accreditation guidelines in 2009. This study's findings suggest a need for both the development and the evaluation of more robust policies and programs to create a physician workforce that is demographically representative of the US population.
P14.60 FET PET response upon radiochemotherapy followed by Tumor Treating Fields (TTFields) in a patient with progressive high-grade glioma
Authors: A F Keßler, J Weiland, T Linsenmann, R Ernestus, C Hagemann, M Löhr
Journal: Neuro-Oncology (2019)

Abstract BACKGROUND The addition of Tumor Treating Fields (TTFields) to the first-line therapy in glioblastoma (GBM) demonstrated significantly improved progression free survival, overall survival and longterm survival rates in the EF-14 phase 3 trial. However, responder analysis of patients with recurrent GBM (rGBM) treated with TTFields monotherapy (in the EF-11 trial) revealed delayed response monitored by MRI analysis. More recent data suggests that O-(2-18F-fluoroethyl)-L-tyrosine (FET) PET may add valuable information for monitoring therapy response of glioblastoma patients treated with TTFields. Here, we report on FET PET response in a patient with progressive anaplastic astrocytoma WHO grade III (AA) treated with TTFields in combination with temozolomide (TMZ) chemotherapy. METHODS We present a 38-year old patient with an initial diagnosis of a diffuse astrocytoma WHO grade II in 2011, and malignisation to an AA on progression. The treatment regimen included initially radio-chemotherapy (RCT) with TMZ. On further progression of the AA in 2017, TTFields were added to another 6 cycles of TMZ. Several FET PET scans for differentiation of tumor progression from treatment-related changes were performed over time. The definitive diagnosis (tumor progression and grading) was confirmed by histopathology after stereotactic biopsy (SB). RESULTS In 2012, the patient was first diagnosed with a low grade astrocytoma WHO grade II of the right frontal, temporal and parietal lobe including infiltration of thalamus and corpus was confirmed by SB, followed by irradiation. On progression in 2015, a FET PET Scan showed FET avidity in all tumor affected regions of the brain. SB confirmed an AA, while FET PET scans showed only a mild response in the temporoparietal region after 6 cycles of TMZ. In 2017, the next progression without further malignisation was confirmed by SB and treated RCT with 41.4 Gy and TMZ chemotherapy, followed by application of TTFields with an average usage rate of 85.7 % over 6 months. Thus, the TTFields adherence was well above the independent prognostic threshold of 75 %. No additional adverse events due to the combined therapy of TTFields and TMZ were observed. Due to a new contrast enhancing lesion in the right frontal lobe (10x7mm), another FET PET scan was performed 1.5 years later. In this scan, obtained after combined TTFields and RCT therapy a strong response regarding FET avidity was observed. CONCLUSION In summary, FET PET is able to add important additional information for evaluation of treatment response in high grade glioma patients, in particular for TTFields treated patients, while adding TTFields to radiochemotherapy might even enhance treatment response of high grade glioma. Further studies might elucidate the role of FET PET imaging for therapy monitoring in high grade glioma patients treated with TTFields.
Peptide-conjugated oligonucleotides evoke long-lasting myotonic dystrophy correction in patient-derived cells and mice
Authors: Arnaud F. Klein, Miguel A. Varela, Ludovic Arandel, Ashling Holland, Naira Naouar, Andrey Arzumanov, David Seoane, Lucile Revillod, Guillaume Bassez, Arnaud Ferry, Dominic Jauvin, Genevieve Gourdon, Jack Puymirat, Michael J. Gait, Denis Furling, Matthew J.A. Wood
Journal: Journal of Clinical Investigation (2019)

Antisense oligonucleotides (ASOs) targeting pathologic RNAs have shown promising therapeutic corrections for many genetic diseases including myotonic dystrophy (DM1). Thus, ASO strategies for DM1 can abolish the toxic RNA gain-of-function mechanism caused by nucleus-retained mutant DMPK (DM1 protein kinase) transcripts containing CUG expansions (CUGexps). However, systemic use of ASOs for this muscular disease remains challenging due to poor drug distribution to skeletal muscle. To overcome this limitation, we test an arginine-rich Pip6a cell-penetrating peptide and show that Pip6a-conjugated morpholino phosphorodiamidate oligomer (PMO) dramatically enhanced ASO delivery into striated muscles of DM1 mice following systemic administration in comparison with unconjugated PMO and other ASO strategies. Thus, low-dose treatment with Pip6a-PMO-CAG targeting pathologic expansions is sufficient to reverse both splicing defects and myotonia in DM1 mice and normalizes the overall disease transcriptome. Moreover, treated DM1 patient-derived muscle cells showed that Pip6a-PMO-CAG specifically targets mutant CUGexp-DMPK transcripts to abrogate the detrimental sequestration of MBNL1 splicing factor by nuclear RNA foci and consequently MBNL1 functional loss, responsible for splicing defects and muscle dysfunction. Our results demonstrate that Pip6a-PMO-CAG induces long-lasting correction with high efficacy of DM1-associated phenotypes at both molecular and functional levels, and strongly support the use of advanced peptide conjugates for systemic corrective therapy in DM1.
RNA-Seq profiling of circular RNA in human lung adenocarcinoma and squamous cell carcinoma
Authors: Chengdi Wang, Shuangyan Tan, Wen-Rong Liu, Qian Lei, Wenliang Qiao, Yangping Wu, Xiaoqi Liu, Wei Cheng, Yu-Quan Wei, Yong Peng, Weimin Li
Journal: Molecular Cancer (2019)

Emerging evidences demonstrate that circular RNAs (circRNAs) are abnormally expressed in tumors and could serve as prognostic markers for cancers. However, the expression patterns and clinical implications of circRNAs in non-small cell lung cancer (NSCLC) remain obscure. In this study, we profiled circRNA expressions in 10 pairs of lung adenocarcinoma (LUAD) and squamous cell carcinoma (LUSC) after ribosomal RNA-depletion and RNase R digestion to enrich circRNAs. Combining five circRNA computational programs, we found that LUAD and LUSC not only share common expression patterns, but also exhibit distinct circRNA expression signatures. Moreover, the Receiver Operating Characteristic (ROC) curve analysis indicated that hsa_circ_0077837 and hsa_circ_0001821 could serve as potential biomarkers for both LUAD and LUSC, while hsa_circ_0001073 and hsa_circ_0001495 could be diagnostic/subtyping marker for LUAD and LUSC, respectively. Therefore, our findings highlight the important diagnostic potential of circRNAs in NSCLC.
Oncogenic KRASG12D in the Hematopoietic System Causes NLRP3 Inflammasome Activation Leading to Myeloproliferative Syndrome
Authors: Shaima'A Hamarsheh, Miriam Erlacher, Lena Osswald, Oliver Gorka, Justus Duyster, Olaf Groß, Claudia Lengerke, Melanie Börries, Tilman Brummer, Robert Zeiser
Journal: Blood (2018)
New UK guidelines for the management of adult patients with ARDS
Authors: Mark Griffiths, Eddy Fan, Simon V Baudouin
Journal: Thorax (2019)

Acute respiratory distress syndrome (ARDS) was first reported in a case series from Denver in 1967,1 and remains a major problem in the severely ill. This was highlighted by data from the recently published Large observational study to UNderstand the Global impact of Severe Acute respiratory FailurE (LUNG SAFE) trial, which recorded admissions over 4 weeks to 459 intensive care units (ICUs) in 50 countries and included 29 144 patients. In total, 3022 (10.4%) cases fulfilled ARDS criteria, including almost a quarter of those supported with invasive mechanical ventilation.2 ARDS was associated both with high mortality and prolonged length of stay. In addition, long-term follow-up studies of patients with ARDS indicate high long-term morbidity and decreased quality of life.3 There is therefore a real need to improve outcomes in ARDS.

With this aim in mind, the Intensive Care Society (ICS)/Faculty of Intensive Care Medicine (FICM) guideline for the management of the ARDS in adults was published towards the end of 2018.4 The multidisciplinary Guideline Development Group used Grading of Recommendations Assessment, Development and Evaluation (GRADE) methodology.5 The group allocated selected outcomes as being either of critical (mortality up to 1 year, quality of life at 3 months) or high importance (quality of life at 6–12 months, length of ICU and hospital stay and treatment-associated harms). Ten interventions used in patients with ARDS were examined, based on existing recommendations and the experience of committee members, and informed by a survey of ICS members. The evidence-based findings are summarised in table 1. Two strong recommendations (using GRADE terminology) in favour of interventions and one strong recommendation against an intervention were made. Where mechanical ventilation is required, the use of low tidal volumes (<6 mL/kg ideal body weight) and airway pressures (plateau pressure <30 cmH2O) was recommended. For …
P14.56 Recurrent Glioblastomas: Should we operate a second and even a third time
Authors: M Yahia-Cherif, O De Witte, C Mélot, F Lefranc
Journal: Neuro-Oncology (2019)

Abstract BACKGROUND The aim of this study was i) to analyse the effect of repeat surgeries on the survival of patients with focally recurrent glioblastoma who have benefited from temozolomide treatment and ii) to identify potential prognostic factors for survival. MATERIAL AND METHODS Cases from 2005 to 2014 in the glioblastoma database of our department were retrospectively reviewed. The Kaplan-Meier method was used to estimate overall survival (OS) as a function of time after one, two and three surgical resections. All patients received the standard of care after the first surgery (temozolomide during and after radiotherapy) and adjuvant treatment after repeat surgeries. RESULTS One hundred-thirty-two glioblastoma patients (median age: 57 years) were included in the study. Among them, 68, 53 and 11 patients underwent one, two and three surgical resections, respectively. The median OS was 11, 16 and 18 months, respectively, for patients who underwent one, two and three surgical resections. Patients who underwent two (p&lt;0.001) or three (p&lt;0.01) surgeries survived significantly longer than patients who underwent only one. No significant difference was observed between patients who underwent two versus three surgeries (p=0.76). A second resection performed more than 6 months after the initial resection was the only factor associated with prolonged survival (p=0.008). CONCLUSION Glioblastoma patients who benefited from temozolomide treatment and underwent surgery for recurrent glioblastoma exhibited a significant increase in survival compared with patients who did not undergo a second surgery. By contrast, a third surgery for a second recurrence did not contribute to any significant survival benefit.