tbuckley/cabot-search huggingface dataset:
P14.121 Use of corticosteroids in glioblastoma patients A single institution experience
Authors: U Smrdel, M Skoblar Vidmar
Journal: Neuro-Oncology (2019)

Abstract INTRODUCTION Corticosteroids are group of drugs widely used in patients with glioblastoma. As they control peritoumoral oedema, virtually all patients are at some time receiving one. Though, they are effective drugs, their use comes with many side effects affecting the QoL, and might even have a detrimental effect on survival. PATIENTS AND METHODS We collected the data of patients treated for glioblastoma in Slovenia between 1997 and 2016. In our database of 1051patients, we calculated the survival and progression free survival. Then we checked the corticosteroid use for every individual patient at the time of referral, beginning of radiotherapy (RT), completion of RT, at 3 and 6 months. We stratified patients according to the resection extent, performance status, age groups, and treatment intent. We also looked for any adverse effect which could be connected to corticosteroid usage. Due to historical circumstances, we did not have a peroral dexamethasone in Slovenia until 2012, so patients regularly received methyl prednisolone instead, though they received parenteral dexamethasone. We are reporting all corticosteroid doses calculated and expressed in milligrams of dexamethasone. RESULTS At the time of referral, 90 % of patients received corticosteroids. Median dose was 4 mg of dexamethasone 2 times daily (0 to 8 mg 3 times daily). In around half of patients, dexamethasone could be lowered prior to radiotherapy. Factors preventing early tapering were: biopsy only, higher age and performance status. Tapering of dexamethasone than continued after completion of RT. Beside corticosteroid diabetes, proximal myopathy was the most frequent adverse effect, followed by osteoporosis. The group of patients, surviving more than 3 years, had significantly lower dose of corticosteroids at the end of RT than other patients, while there was no difference in dose at the time of referral and afterwards. Tapering of the dose was quicker with the younger patients and also when patients received methyl prednisolone. The patients receiving methyl prednisolone also had more problems with osteoporosis. DISCUSSION Our data confirms the benefits and dangers of corticosteroid usage. While all are aware of the corticosteroid diabetes and osteoporosis, the myopathy was most commonly expressed complaint in our patients and might be underreported, especially, when weakness might also be attributed to underlying disease. Not only, is the higher dose of dexamethasone associated with more common and more severe adverse affects, but one could question if there is more direct connection of corticosteroids and survival. CONCLUSION While the corticosteroids remain essential medications in glioblastoma patients, they should be used with care. Tapering of the corticosteroids should start as early as possible. Balance between the beneficial effects of corticosteroids and their detrimental effects should be reached.
Serial Lineage Chimerism Analysis Improves Early Diagnosis of Graft Failure after Allogeneic HSCT
Authors: Ignacio Gómez-Centurión, Mi Kwon, Pascual Balsalobre, David Serrano, Nieves Dorado Herrero, Laura Solán, María Chicano Lavilla, Diego Carbonell, Jose Luis Díez-Martín, Carolina Martínez-Laperche, Ismael Buño
Journal: Blood (2018)
Splicing factor SRSF1 controls T cell hyperactivity and systemic autoimmunity
Authors: Takayuki Katsuyama, Hao Li, Denis Comte, George C. Tsokos, Vaishali R. Moulton
Journal: Journal of Clinical Investigation (2019)

Systemic lupus erythematosus (SLE) is a devastating autoimmune disease in which hyperactive T cells play a critical role. Understanding molecular mechanisms underlying the T cell hyperactivity will lead to identification of specific therapeutic targets. Serine/arginine-rich splicing factor 1 (SRSF1) is an essential RNA-binding protein that controls posttranscriptional gene expression. We have demonstrated that SRSF1 levels are aberrantly decreased in T cells from patients with SLE and that they correlate with severe disease, yet the role of SRSF1 in T cell physiology and autoimmune disease is largely unknown. Here we show that T cell–restricted Srsf1-deficient mice develop systemic autoimmunity and lupus-nephritis. Mice exhibit increased frequencies of activated/effector T cells producing proinflammatory cytokines, and an elevated T cell activation gene signature. Mechanistically, we noted increased activity of the mechanistic target of rapamycin (mTOR) pathway and reduced expression of its repressor PTEN. The mTOR complex 1 (mTORC1) inhibitor rapamycin suppressed proinflammatory cytokine production by T cells and alleviated autoimmunity in Srsf1-deficient mice. Of direct clinical relevance, PTEN levels correlated with SRSF1 in T cells from patients with SLE, and SRSF1 overexpression rescued PTEN and suppressed mTORC1 activation and proinflammatory cytokine production. Our studies reveal the role of a previously unrecognized molecule, SRSF1, in restraining T cell activation, averting the development of autoimmune disease, and acting as a potential therapeutic target for lupus.
P11.36 Ribosome hydroxylase Mina53 is required for Glioblastoma and is involved in regulation of translation rateand fidelity by regulating ribosomal biogenesis
Authors: D Pandey, F Mohammad, S Weissmann, P Hallenborg, B Blagoev, K Helin
Journal: Neuro-Oncology (2019)

Abstract Glioblastoma multiforme (GBM) is one of the most aggressive types of tumors with a poor response to standard treatment and a median 5-year survival of less than 5%. Therefore, there is an urgent need for new treatments. Recently, a large number of genome-wide studies have shown that the epigenetic modifiers are frequently deregulated in cancer. Using a mouse GBM model, we performed in vitro and in vivo shRNA screens to identify epigenetic regulators required for the tumorigenic process in GBM. Among these regulators is a ribosome hydroxylase Mina53 which hydroxylates His-39 of ribosomal protein, RPL27a. We have found that the knock-down (KD) of Mina53 reduces the in vitro proliferation and colony forming ability of mouse glioma initiating cells (mGIC) and this is dependent on the catalytic activity of Mina. Knock-down of Mina resulted into a small but significant reduction in the global protein synthesis rate. A tandem affinity purification experiment to identify proteins associated with Mina revealed that it is associated mainly with ribosomal proteins, including its substrate RPL27a. Global proteomic analyses revealed that final amounts and de novo protein synthesis of many ribosomal proteins were reduced upon Mina depletion. Isolation and identification of different polysome fraction bound mRNAs using high-throughput sequencing found that mRNAs encoding many ribosomal proteins have lower number of ribosomes loaded on them in the Mina depleted samples compared to the control. Taken together, this study has found that Mina53 is required for glioblastoma and it regulates translation through regulation of ribosomal biogenesis
Chimeric antigen receptor–induced BCL11B suppression propagates NK-like cell development
Authors: Marcel Maluski, Arnab Ghosh, Jessica Herbst, Vanessa Scholl, Rolf Baumann, Jochen Huehn, Robert Geffers, Johann Meyer, Holger Maul, Britta Eiz-Vesper, Andreas Krueger, Axel Schambach, Marcel R.M. van den Brink, Martin G. Sauer
Journal: Journal of Clinical Investigation (2019)

The transcription factor B cell CLL/lymphoma 11B (BCL11B) is indispensable for T lineage development of lymphoid progenitors. Here, we show that chimeric antigen receptor (CAR) expression during early phases of ex vivo generation of lymphoid progenitors suppressed BCL11B, leading to suppression of T cell–associated gene expression and acquisition of NK cell–like properties. Upon adoptive transfer into hematopoietic stem cell transplant recipients, CAR-expressing lymphoid progenitors differentiated into CAR-induced killer (CARiK) cells that mediated potent antigen-directed antileukemic activity even across MHC barriers. CD28 and active immunoreceptor tyrosine–based activation motifs were critical for a functional CARiK phenotype. These results give important insights into differentiation of murine and human lymphoid progenitors driven by synthetic CAR transgene expression and encourage further evaluation of ex vivo–generated CARiK cells for targeted immunotherapy.
P08.03 Separation and divorce after the diagnosis of child’s brain tumor
Authors: I Sardi, M Censullo, M Rousseau, M Guidi, F Giordano, C Fonte, S Farina, F Carra, L Genitori
Journal: Neuro-Oncology (2019)

Abstract BACKGROUND The diagnosis of a child’s brain tumor is a terrible situation for every member of the family. Numerous are the case of separations and divorces in Italy after a diagnosis of a child’s cancer. In particular, it happens with parents of children affected with brain tumor, being the most frequent solid tumor and the first cause of a tumor child’s death. The crisis related to the discovery of a tumor consists of four phases: shock, reaction, processing and re-orientation. It can happen that the diagnosis, experienced as a traumatic experience, can unite the family members as well as separate them. If there is already a process of family disintegration, a trauma can be a cause for breakup. The aim of our study was to investigate the possible correlation between brain tumor diagnosis in children and parental separations/divorces. MATERIAL AND METHODS We considered 427 patients afferent from 2012 to 2018 to the Neuro-Oncology Unit of the Meyer Children’s Hospital. Brain tumors are the 55–60% of all the tumors of our hospital, with an extra-regionality greater than 65%. The data analysis was conducted through information obtained directly from the families during follow-up visits or by telephone interviews. RESULTS Consistent with literature data in our series, the most frequent brain tumors were low-grade gliomas medulloblastomas, high-grade gliomas, ependymomas, midline diffuse gliomas, craniopharyngiomas, germ cell tumors and other rare pediatric tumors. The population was divided in 16 females and 18 males from different Italian regions: 65% from Central Italy, 23% from the South and Islands, 12% from the North. Data analysis showed 34 cases of separation and/or divorce, equal to 7% of our whole population, during treatment and more frequently at the end of treatment or after death. The median age of the 34 patients at the diagnosis of brain tumor was 9.5 years (range 1–19 years), with a higher percentage of cases of separations (41%) for parents of patients aged 10 years-14 years; 7 were the cases of separation and/or divorce when the diagnosis of brain tumor was made around 12–48 months after the child birth. CONCLUSION The diagnosis of a child’s brain tumor can generate stress in the family leading to different reactions, such as conflicts between parents or a real family crisis. The results of our study suggest a possible correlation between the diagnosis of a child’s brain tumor and the cases of separation and/or divorce. High risk medulloblastomas and high-grade gliomas that are likely to have a shorter path due to the unfavorable prognosis of the disease, appear to be the pathologies more often related to situations of family disputes. However, further investigations are necessary to verify the trend emerged from our study respect to the normal population.
P14.67 Somatostatin receptor targeted radioligand therapyin head and neck paraganglioma
Authors: M Müther, W Roll, L Stegger, B Zinnhardt, M Schäfers, M Weckesser, K Rahbar, W Stummer
Journal: Neuro-Oncology (2019)

Abstract BACKGROUND Surgical resection is the therapy of choice in head and neck paraganglioma. However, surgery is associated with significant morbidity depending on tumor size and localization. In case of progressive residual or recurrent disease, new and less aggressive therapeutic options are warranted. Somatostatin receptor (SSTR) targeted therapies pose a promising alternative, as SSTRs are upregulated in paragangliomas. Only few studies provide evidence on efficacy of 177Lu-DOTATATE therapy in these patients. The aim of this study was to evaluate the efficacy of peptide receptor radiotherapy (PPRT) with 177Lu-DOTATATE for head and neck paragangliomas. METHODS A total of seven consecutive patients (mean age: 60 years, range: 14–84) with progressive head and neck paragangliomas (3 carotid body tumors, 4 jugulotympanic paragangliomas), treated with PRRT using 177Lu-DOTATATE, were included in this retrospective analysis. Therapy response was assessed by interim and post-therapy 68Ga-DOTATATE-PET-CT and MRI according to morphological and SSTR imaging parameters. Therapeutic uptake was classified on177Lu-DOTATATE scintigraphies 48h p.i. according to the Krenning scale. Longer-term clinical and imaging-based outcome were evaluated. RESULTS Patients received a median of 4 cycles (range: 3 to 5) of PRRT with 177Lu-DOTATATE (mean injected dose 7.3 GBq). Interim and post-therapy staging showed at least stable disease in all patients. Tumor uptake in 48h p.i. 177Lu-scintigraphies was moderate to high in all patients (Krenning scale; median: 3; range: 2–4). Furthermore, none of the patients showed progressive disease during the median follow-up time of 28 months (range: 6–37 months). CONCLUSION SSTR targeted therapy using 177Lu-DOTATATE shows promising efficacy and may lead to long lasting stable disease.
Global patterns and trends in colorectal cancer incidence in young adults
Authors: Rebecca L Siegel, Lindsey A Torre, Isabelle Soerjomataram, Richard B Hayes, Freddie Bray, Thomas K Weber, Ahmedin Jemal
Journal: Gut (2019)

Objective Early-onset colorectal cancer (CRC) is increasing in the USA despite rapid declines in older ages. Similar patterns are reported in Australia and Canada, but a comprehensive global analysis of contemporary data is lacking. Design We extracted long-term data from Cancer Incidence in Five Continents and supplemental sources to report on worldwide CRC incidence rates and trends by age (20–49 years and ≥50 years) through diagnosis year 2012 or beyond (Australia, Finland, New Zealand, Norway, Sweden, USA). Results During 2008–2012, age-standardised CRC incidence rates in adults &lt;50 ranged from 3.5 per 100 000 (95% CI 3.2 to 3.9) in India (Chennai) to 12.9 (95% CI 12.6 to 13.3) in Korea. During the most recent decade of available data, incidence in adults &lt;50 was stable in 14 of 36 countries; declined in Austria, Italy and Lithuania; and increased in 19 countries, nine of which had stable or declining trends in older adults (Australia, Canada, Denmark, Germany, New Zealand, Slovenia, Sweden, UK and USA). In Cyprus, Netherlands and Norway, inclines in incidence in young adults were twice as rapid as those in older adults (eg, Norway average annual per cent change (AAPC), 1.9 (95% CI 1.4 to 2.5) vs 0.5 (95% CI 0.3 to 0.7)). Among most high-income countries with long-term data, the uptick in early-onset disease began in the mid-1990s. The steepest increases in young adults were in Korea (AAPC, 4.2 (95% CI 3.4 to 5.0)) and New Zealand (AAPC, 4.0 (95% CI 2.1 to 6.0)). Conclusion CRC incidence increased exclusively in young adults in nine high-income countries spanning three continents, potentially signalling changes in early-life exposures that influence large bowel carcinogenesis.
Persistent Basal Cell Hyperplasia Is Associated With Clinical and Endoscopic Findings in Patients With Histologically Inactive Eosinophilic Esophagitis
Authors: Kelly A. Whelan, Bridget C. Godwin, Benjamin Wilkins, Okan U. Elci, Alain Benitez, Maureen DeMarshall, Medha Sharma, Jonathan Gross, Andres J. Klein-Szanto, Chris A. Liacouras, Evan S. Dellon, Jonathan M. Spergel, Gary W. Falk, Amanda B. Muir, Hiroshi Nakagawa
Journal: Clinical Gastroenterology and Hepatology (2019)
Effect on pain outcomes in patients treated for painful bone metastases with biopolar RFA: The OPuS One study.
Authors: Sandeep Bagla, Jason Levy, Thomas Hopkins
Journal: Journal of Clinical Oncology (2019)

11605 Background: To report the preliminary outcomes from the prospective, nonrandomized, multicenter study of the OsteoCool Radiofrequency Ablation system used for the palliative treatment of patients with painful bone metastases (OPuS One Study). Methods: Subjects were prospectively enrolled (NCT03249584) from October 2017 through August 2018. Inclusion criteria were: 2 or less painful target sites involving the thoracolumbar spine, pelvis and/or sacrum, with a worst pain ≥4/10 measured by the Brief Pain Inventory (BPI) within the previous 24 hours. RFA was performed with the OsteoCool device (Medtronic) under imaging guidance and followed by cementoplasty at operator discretion. Subjects were evaluated prior to RFA, at discharge, 3 days, 1 week, and 1-, 3-, 6-, and 12-months. Demographics and disease characteristics were collected at baseline and outcomes were assessed using validated measures. Device-, procedure- and/or therapy-related adverse events (AEs) were collected. Results: At the time of the analysis, 37 subjects at 8 US centers underwent RFA. The mean age was 64 years (range 30-89) and 68% were female. Mean baseline BPI worst pain was 8.6. The most common histology was adenocarcinoma; breast (32%) and lung (24%) were reported as the most common primary cancer. Thirty-one subjects (84%) were treated for lesions involving the thoracolumbar spine, while 6 subjects (16%) were treated for lesions located the pelvis and/or sacrum. All RFA procedures were technically successful. Of the 14 subjects presenting at the 3-month visit, 93% did not undergo radiation therapy at the targeted site(s) between baseline and 3 months. Seventy-four percent (25/34) of subjects at 1 week and 93% (13/14) of subjects at 3 months reported a clinically significant change from baseline in worst pain of ≥ 2 points. One AE, drug hypersensitivity, resolved without intervention. All eleven deaths reported were attributed to the subjects underlying malignancy and not related to RFA. Conclusions: The preliminary results of the OPuS One study show rapid pain improvement at 1 week and sustained long-term relief through 3 months in patients with metastatic bone disease. Clinical trial information: NCT03249584.
Medical oncologists’ experience with returning molecular tumor profiling to patients.
Authors: Subotheni Thavaneswaran, Christine Napier, David Goldstein, Bettina Meiser, Phyllis Butow, David Morgan Thomas, Mandy L. Ballinger, Megan Best
Journal: Journal of Clinical Oncology (2019)

10521 Background: Molecular tumor profiling (MTP) to guide therapy is increasingly being applied in the clinic, although how medical oncologists (MOs) manage this in clinical practice is not fully understood. Methods: An online survey explored MOs’ experience with MTP interpretation, treatment (tx) decisions, identifying resources, and communicating results to patients with cancer. MOs were identified based on their participation in the Australian Molecular Screening and Therapeutics Program. Results: 108 MOs (57% male, median years of practice, 5-9 years, 83% urban-based practice and median age range, 40-49 years) participated from June 2018 – Jan 2019. Most MOs had experience with MTP (90%), and felt it was their role to discuss results. MOs felt confident discussing the process of MTP, the probability of a ‘therapeutically actionable finding’, and results (score 70-75, range 0 least confident - 100 completely confident). However, almost two-thirds of MOs needed/wanted assistance with interpretation of results, favouring a Family Cancer Clinic (FCC) helpline, patient information sheets on MTP, and decision aids. In particular, MOs were less confident discussing germline results and their implications (median score 56) but were comfortable (median score 96) to refer to an FCC. Most MOs felt there was sufficient information on the MTP report to understand results. Some preferred to receive ‘all cancer gene variants’ (36%), others only those with clinical actionability (45%), and some only those with therapeutic actionability (19%). Most MOs (85%) wanted to know the full list of genes assayed, tx recommendations, and/or a list of relevant trials. Interestingly, MOs indicated little confidence that MTP would guide useful tx decisions (median score 51) and most reserved it for the tx-refractory setting. A minimal level of evidence supporting treatment was required by 83% of MOs prior to recommending biomarker-guided tx. Conclusions: MOs are increasingly integrating MTP into clinical practice, despite uncertainty about result validity and clinical translation, particularly regarding germline results. Understanding these potential barriers is the first step in developing clinician supports to facilitate clinical translation.
Almost half of consultant anaesthetists have had a car accident or near miss on their commute home because of fatigue
Authors: Abi Rimmer
Journal: BMJ (2019)

A survey of consultants in anaesthesia and paediatric intensive care working in the UK and Ireland found that most had experienced work related fatigue.

The survey, published in Anaesthesia ,1 received 3847 responses from consultants working in the UK and the Republic of Ireland (a 46% response rate).

Of those, 3792 (98.5%) worked in the UK and 56 (1.5%) in Ireland. Most (91%) said that they had experienced work related fatigue and 72% said that this had a moderate or significant negative impact on their social and family life.

The survey found that while 79% of consultants …
A Terminal Event
Authors: Andrew R. Lai, Leslie Sheu, Lianne S. Gensler, Kenneth McQuaid, Gurpreet Dhaliwal
Journal: New England Journal of Medicine (2019)

A 54-year-old man presented with a 2-year history of constant, nonradiating lumbar pain. Over the 6 months before this presentation, severe back pain frequently awakened him from sleep. He reported no fevers, chills, weight loss, or gastrointestinal or urinary symptoms.
John Henderson: paediatric respiratory epidemiologist and clinical scientist
Authors: Alan Craft
Journal: BMJ (2019)

John Henderson, who has died at the age of 61, was an outstanding paediatrician and clinical scientist. The latter is someone who not only provides excellent care to his patients but delves deeper to try to find the reasons behind their problems. They form a bridge between clinicians and laboratory scientists, making sure that they answer clinically relevant questions, and bring cutting edge science to the bedside.

Henderson specialised in diseases of the respiratory system, and after training in the UK and Australia he was appointed as a consultant in Bristol and led an excellent regional service for many years. He was a superb clinician and ensured that his patients had the most up to date and effective treatments for their condition. 

One of his major interests was asthma, which affects one in 10 children, or 1.1 million across the UK. It causes many deaths, and it is estimated that the NHS spends more than £1bn (€1.1bn; $1.2bn) on treating asthma each year. But, although asthma was a major part of his work, Henderson was active wherever children had breathing problems. He was especially proud of the retrieval service that he set up to bring patients from the far reaches of Devon and Cornwall, ensuring that they …