tbuckley/cabot-search huggingface dataset:
PL3.1 A phase 1, open-label, perioperative study of ivosidenib (AG-120) and vorasidenib (AG-881) in recurrent, IDH1-mutant, low-grade glioma: results from cohort 1
Authors: I K Mellinghoff, P Y Wen, J W Taylor, E A Maher, I Arrillaga-Romany, K B Peters, K Le, F Tai, L Steelman, T F Cloughesy
Journal: Neuro-Oncology (2019)

Abstract BACKGROUND Mutant isocitrate dehydrogenase (mIDH) enzymes produce the oncometabolite D-2-hydroxyglutarate (2-HG). Ivosidenib (IVO; AG-120) is a first-in-class oral inhibitor of mIDH1 being evaluated in 66 glioma patients (pts) in an ongoing phase 1 study (NCT02073994). Vorasidenib (VOR; AG-881) is an oral, potent, brain-penetrant inhibitor of mIDH1/2 being evaluated in 52 glioma pts in an ongoing phase 1 study (NCT02481154). In an orthotopic glioma model, IVO and VOR reduced 2-HG levels by 85% and 98%, respectively, despite different brain:plasma ratios (&lt;0.04 vs 1.33). MATERIAL AND METHODS This is a phase 1, multicenter, open-label, perioperative study (NCT03343197). Pts with recurrent, nonenhancing WHO 2016 Grade (Gr) 2 or 3 mIDH1-R132H oligodendroglioma or astrocytoma undergoing craniotomy were randomized 2:2:1 to IVO 500 mg QD, VOR 50 mg QD, or no treatment (control) for 4 wk preoperatively in Cohort 1. Postoperatively, pts continued to receive IVO or VOR, and control pts were randomized 1:1 to IVO or VOR. Tumors were assessed for mIDH1 status, cellularity, 2-HG, and drug concentration. Treated samples were compared with control pts and mIDH1 and wild type (WT) banked reference (ref) samples. Plasma and CSF 2-HG were assessed. Primary endpoint: brain tumor 2-HG concentration with IVO or VOR treatment. Pts with nonevaluable tissue were replaced. RESULTS As of 29 Nov 2018, 26 pts (17 men, 9 women; 25 Gr 2, 1 Gr 3) were randomized preoperatively (IVO 10, VOR 11, control 5) and 25 received drug (IVO 12, VOR 13). At the data cut, 19 tumors were analyzed, with 16 evaluable. Treatment-emergent adverse events in &gt;10% of patients (all Gr 1 or 2) were diarrhea (36%); hypocalcemia and constipation (each 20%); anemia, hyperglycemia, pruritus, headache, and nausea (each 16%); and hypokalemia and fatigue (each 12%). Mean brain:plasma ratio was 0.16 for IVO and 2.4 for VOR. Geometric mean (range) tumor 2-HG levels (μg/mL) were: IVO (n=6), 10 (2.2-104); VOR (n=6), 6.8 (3.9-10); control mIDH1 (n=65 [4 pts, 61 ref]), 141 (4.8-909); and WT ref (n=15), 2.7 (0.46-12). Mean changes (95% CI) in 2-HG level vs control were IVO -93% (74%, 98%) and VOR -95% (82%, 99%). Updated data from Cohort 1 will be presented. CONCLUSION In Cohort 1 of this phase 1 perioperative study, IVO and VOR were CNS penetrant and lowered tumor 2-HG levels compared with untreated samples. Cohort 2 is open and will evaluate IVO 250 mg BID and VOR 10 mg QD. FUNDING Agios Pharmaceuticals, Inc.
Corrigendum to ‘Nigerian surgical outcomes – Report of a 7-day prospective cohort study and external validation of the African surgical outcomes study surgical risk calculator’ [Int. J. Surg. 68 (2019) 148–156]
Authors: Babatunde Osinaike, Omobolaji Ayandipo, Tonia Onyeka, Olubusola Alagbe-Briggs, Alhassan Mohammed, Olanrewaju Oyedepo, Ahmed Nuhu, Felicia Asudo, Olanrewaju Akanmu, Chris Nwokorie, Abdulrahman Mohammed, Mark Edubio, Kodilinye Izuora, Rabiu Mohammed, Onochie Nweze, Michael Efu, Stella Eguma, Abiodun Jasper, Richard Ewah, Irene Akhideno, Chimaobi Nnaji, Suleiman Ado, Elizabeth Ogboli-Nwasor, Mamuda Atiku, Ibrahim Salisu, Yakubu Adinoyi, Edith Agu, Ibironke Desalu, Luka Samuel, Yunus Olorode, Oluwabunmi Fatungase, Olugbenga Akinwonmi, Folayemi Faponle, Olusola Idowu, Erdoo Isamade, Abdulrahman Aliyu, Shanka Buba, Garba Hamza, Bisola Onajin-Obembe, Simbo Amanor-Boadu
Journal: International Journal of Surgery (2019)
P14.59 Post-Market Surveillance Data of the EMEA region indicate good tolerability of TTFields in WHO Grade III Glioma
Authors: A F Keßler, R Ritz
Journal: Neuro-Oncology (2019)

Abstract BACKGROUND Despite considerable progress in molecular characterization and evidence for certain regimens, treatment of grade III gliomas is still ambiguous and, with surgery, radiotherapy and chemotherapy, in analogy to grade IV glioma treatment. Tumor treating fields (TTFields) therapy proved to be effective as an additional anti-mitotic treatment in glioblastoma and is available in several countries. While TTFields in grade III glioma are being investigated in several clinical trials, we report an analysis of surveillance safety data in patients with grade III glioma already treated with TTFields in the EMEA region. METHODS We reviewed post-marketing surveillance data of the EMEA region. Using the MedDRA body system with system organ class and preferred terms, adverse events reported in the subgroup of patients with grade III glioma treated with TTFields were systematically analysed. Patients with diagnosis of anaplastic astrocytoma and anaplastic oligodendroglioma were included. RESULTS This analysis includes 142 patients with grade III glioma treated with TTFields in the EMEA region. Median age was 47 years (range 5–78 years). 64% of the patients reported at least one adverse event. With an incidence of 35%, skin reaction was the most common reported adverse event, none of them were severe. 29 % of the patients reported general disorders, including general health deterioration (15%) and fatigue/malaise (6%). Adverse events related to the nervous system were reported in 26% of patients; seizures were noted in 9% and headache in 7% of patients. CONCLUSION The retrospective analysis of available post-market surveillance data of EMEA patients with grade III glioma showed no occurrence of serious adverse events that were associated with TTFields. Skin reaction, as the most commonly reported adverse event, but also other reported adverse events had comparable incidences to the rates observed in the phase III trials for patients with recurrent (EF-11) and newly diagnosed GBM (EF-14). In summary, this analysis identifies no additional safety signals on the use of TTFields in the treatment of patients with grade III glioma. Future results of clinical trials in these indications will give further insight into safety and efficacy in this subgroup.
Abstract 18827: Left Ventricular Assist Devices and Heart Transplantation Reduces Gut Dysbiosis, Endotoxemia, Inflammation and Oxidative Stress in Advanced Heart Failure Patients
Authors: Melana Yuzefpolskaya, Ryan T Demmer, Pauline N Trinh, Nasrin Akter, Eugene A Royzman, Joseph K Nwokocha, Duygu Onat, Amelia M Zuver, Autumn M Clemons, Alberto Pinsino, Francesco Castagna, Arthur R Garan, Veli K Topkara, Danielle L Brunjes, Koji Takeda, Hiroo Takayama, Yoshifumi Naka, Maryjane A Farr, Anne-Catrin Uhlemann, Paolo C Colombo
Journal: Circulation (2017)

Introduction: Heart failure (HF) is associated with gut dysbiosis (i.e., intestinal overgrowth of pathogenic bacteria, and reduced microbial diversity). Dysbiosis may impair intestinal barrier func...
P04.01 Return to work i patients with low grade glioma
Authors: I Rydén
Journal: Neuro-Oncology (2019)

Abstract BACKGROUND We now treat patients with low-grade gliomas (LGG) more aggressively as this prolong survival. Patients are typically in working age, but their ability to return to work (RTW) following treatment has not been studied. We aimed to study patterns of sick leave and return to work among LGG patients in Sweden. In addition, we explored predictors for RTW following LGG diagnosis. MATERIAL AND METHODS We performed a nationwide register-based study of patients with grade II diffuse LGG. Data on adult patients aged 18–60 years with a histopathological diagnosis of LGG between 2005–2015 were obtained from the Swedish Brain Tumor Registry (n=381). A matched control sample (n=1900) was acquired from Statistics Sweden. Patients and controls were linked to the social insurance agency data for individual information on sick leave and disability compensation. Multivariable logistic regression was used in order to find predictors for RTW. RESULTS One year prior to surgery there was no apparent difference between cases and controls with 90 % working. Among LGG patients there was a rapid increase in sick leave starting approximately six months prior to surgery, while the proportion of controls on sick leave remained constant. One year after surgery, 53 % had returned to work with 29 % working full time. Independent predictors for patients working one year after surgery were higher age (OR 0.96, 95 % CI 0.93–0.99, p &lt;0.01) and more days absent from work prior to procedure (OR 0.91, 95 % CI 0.97-0.95, p &lt;0.001), both negatively associated with RTW. CONCLUSIONS In this cohort, more than half of the patients being diagnosed with LGG RTW within one year. Higher prior absence from work and higher age are risk factors for no-RTW. This study provides new information on rates of and factors influencing RTW in patients with LGG. FUNDING This project was funded by research grant from the Swedish Research Council (2017-00944).
Adar-Mediated Aberrant a-to-I RNA Editing Is Driven By 1q Amplification and Contributes to Proteasome Inhibitor Resistance in Multiple Myeloma
Authors: Alessandro Lagana, Violetta Leshchenko, David Melnekoff, Itai Beno, Deepak Perumal, Jonathan Keats, Mary DeRome, Jennifer Yesil, Daniel Auclair, Deepu Madduri, Ajai Chari, Hearn Jay Cho, Bart Barlogie, Sundar Jagannath, Joel Dudley, Samir Parekh
Journal: Blood (2017)
OS6.1 Targeting Purine Metabolism to Overcome Therapeutic Resistance in Glioblastoma
Authors: A U Ahmed, J Shireman, F Atashi, M Saathoff, E Ali, G Lee, C Park, S Savchuk, J Rayyan, C James, I Ben-Sahra
Journal: Neuro-Oncology (2019)

Abstract BACKGROUND A distinguishing characteristic of all cancers is uncontrolled cell division, and they require additional nucleotide bases such as purines, the building blocks of DNA and RNA, to sustain their uncontrolled growth. Purines can be synthesized from scratch by de novo pathway or salvaged by recycling surrounding nucleotides that are released by hydrolytic degradation. Even though the central nervous system (CNS), as well as CNS associated malignancies like glioblastoma (GBM), rely more heavily on the salvage pathway due to its energy efficiency, its precious role in promoting chemoresistance and GBM recurrence is yet to be elucidated. MATERIAL AND METHODS We have examined the role of purine biosynthesis in GBM by using stable isotope tracing analysis as well as utilizing a knockdown (KD) system to investigate its effect on i) DNA damage response during temozolomide (TMZ) therapy, ii) tumor engraftment and iii) therapeutic responses in vivo. RESULTS Through gene expression and protein-protein interaction analysis, we have identified ARL13B, member of ADP-ribosylation factor-like protein family, as a novel regulator of the purine biosynthesis pathway in GBM. ARL13B can physically interacting with the inosine monophosphate dehydrogenase 2 (IMPDH2), a key rate-limiting enzyme for purine biogenesis. Isotope tracer analysis under normal physiological conditions revealed that during TMZ treatment, salvage recycling activity was decreased by 50% while de novo pathway activity remains unchanged. In contrast, TMZ treatment of ARL13B knock-out cells results in a ~50% decrease in de novo pathway activity (p-value=0.004), whereas purine salvage pathway activity is upregulated ~6-fold (p-value &lt;0.0001). ARL13B knockdown cells treated with TMZ show a robust increase in DNA double-strand breaks compared to control cells exposed to TMZ, as demonstrated by gH2X staining. Mice orthotopically engrafted with KD cells experience prolonged survival relative to mice engrafted with unmodified cells. CONCLUSION We propose that ARL13B-IMPDH2 interaction has two consequences: i) augmentation of de novo purine biosynthesis activity, and ii) inhibition of nucleotide recycling. The increasing de novo purine biosynthesis during TMZ therapy helps GBM cells reduce the recycling of nucleotides via the salvage pathway that have been modified as a result of TMZ alkylation. This, in turn, protects the cells from deleterious effects of incorporating modified nucleotides into newly-synthesized DNA while maintaining a supply of purine building blocks to support uncontrolled proliferation. Our results indicate that the interaction of ARL13B-IMPDH2 functions as a purine biosynthesis regulator that could be targeted for increasing efficacy of TMZ treatment of GBM. ​
P14.123 Neurological complications related to checkpoints inhibitors
Authors: I Esparragosa, R Valenti-Azcarate, D Moreno-Ajona, J Gallego Perez de Larraya
Journal: Neuro-Oncology (2019)

Abstract BACKGROUND Currently, immunotherapy is part of the therapeutic arsenal for oncological treatment. Indeed, the need for new medications has led to the development of immune checkpoint inhibitors. Despite favourable oncological outcomes, these treatments have been associated with immune-related adverse events. Although infrequent, neurological toxicities have been reported. Early recognition is crucial for improvement of functional outcome and requires a multidisciplinary approach. OBJECTIVE To describe a case series of patients with neurological complications related to checkpoint inhibitors. PATIENTS AND METHODS We identified six oncological patients who presented immunomediated neurological complications, derived from the use of checkpoints inhibitors. Five cases were men. Ages ranged from 58 to 73 years. Nivolumab, alone or combined, was the most commonly associated drug (4/6). Underlying diseases included lung carcinoma (2/6), melanoma (2/6), renal carcinoma (1/6) and ovarian adenocarcinoma (1/6). An acute demyelinating sensory-motor polyneuropathy and an acute axonal sensory polyneuropathy were documented in two and one case, respectively. In these, the cerebrospinal fluid analysis revealed albuminocytologic dissociation. All three cases improved after treatment with intravenous immunoglobulins (0.4 g/Kg a day for five days). The latter and another case were diagnosed of aseptic meningitis after cerebrospinal fluid lymphocytic pleocytosis was found. High fever was also associated with lower extremities areflexia, weakness and ataxia. Methylprednisolone (1g/day for five days) was administered. One case of necrotizing inflammatory myositis with high levels of creatine kinasa, confirmed by muscular biopsy, involving cervical weakness and ptosis, was effectively treated with Methylprednisolone (1g/day for five days) follow by oral prednisone tapering. An anti-Yo related pancerebellar syndrome was the only case with a fatal outcome despite treatment. CONCLUSION The increasingly frequent use of immunotherapy in the treatment of cancer may lead to an increase in neurological complications. These include a broad spectrum of syndromes with peripheral nervous system predominantly susceptible. Early identification of these and appropriate management of drug-related toxicity are required. Immune-modulating therapies are particularly beneficial.
OS2.3 Relevance of Neurofibromatosistype 1 and schwannomotosis in extramedullary spine tumors
Authors: M E Eoli, D Bianchessi, M Moscatelli, L Chiapparini, C Ibba, G Finocchiaro, M Bruzzone
Journal: Neuro-Oncology (2019)

Abstract BACKGROUND Extramedullary spine tumors represent two-thirds of all primary spine neoplasms. Approximately half of these are peripheral nerve sheath tumors, mainly neurofibromas and schwannomas and neurofibromatosis or schwannomatosis can be suspected. Given the rarity of this condition the clinical genetic and radiological features remains to be better define. The aim of this study was to characterize the clinical, radiologic presentation of patients with widespread spinal disease and to identify gene mutation. MATERIAL AND METHODS We selected patient with a at least: intradural extramedullary, or extradural intraspinal (tumor within the spinal canal), or extradural paraspinal (tumor at the neural foramenor extending outward into adjacent tissues) neoplasms and no other tumors such as meningiomas in the spine at spine MRI. Patients’ DNA were analyzed by Targeted NGS by means a custom gene panel including NF1, NF2, LZTR1, SMARCB1 genes. RESULTS 63 patients were identified31 had few isolated tumors, involving spinal roots (Multiple Neurofibromas Few Spinal Root, MNFSR), 18 had bilateral neurofibromas involving all spinal roots. 14 had a single lesion; 10 cases were familiar and 53 sporadic. Genetic analysis showed NF1 gene mutations (in prevalence splicing or missense) in 49 cases LZTR1 mutations in 3 and in the others 11 no mutation or deletion was detected. Pain was the hallmark symptom in patients with LZTR1 mutations, while all familial cases all had NF1 diagnosis. About 50% of them had few cutaneous manifestations. CONCLUSION In patients with extramedullary spine tumors is important to look for signs of neurofibromatosis or schawannomatosis and if there are present genetic testing should be performed.
Prospective, randomized, multicentre clinical trial on the use of interferon a 2a plus PUVA versus PUVA monotherapy in patients with cutaneous T-cell lymphoma, stages I and II
Authors: R. Stadler, A. Kremer, T. Luger, W. Sterry
Journal: Journal of Clinical Oncology (2006)

7541 To further define the role of IFN in combination with PUVA we conducted this prospective, randomized, multicentre clinical trial, in cooperation with 26 departments of dermatology in Germany and Switzerland, comparing the efficacy and tolerability of the combination of IFN alfa plus PUVA versus PUVA alone. IFN alfa 2a was administered at 9 Mill units three times a week s.c. in the combination arm, photochemotherapy was applied after oral intake of 8-methoxypsoralen (0.6 mg/kg body weight) five times a week during the first weeks, three times a week from weeks 5 to 23, and twice a week from weeks 24 to 48, with escalating doses, beginning with 0.25J/cm 2 . Of 124 patients randomized in this trial stages I and II, 50 were evaluable in the PUVA arm and 43 in the IFN plus PUVA arm in total 93 patients. Overall 75% of all patients showed a complete remission, 79% in the combination arm and 72% in the PUVA arm. The primary response criteria of this randomized trial protocol as a rate of complete remissions was therefore statistically non significant. However, the total dose of meladinine to reach best response was significantly lower in the combination arm, in the IFN arm only 74% of the meladinine dose and 57% of the UVA dose was necessary to reach a complete remission in comparison to the PUVA arm. The follow-up period was defined was defined on time to progression and documentation maximal 12 months after best response. The medium follow-up duration is 101 weeks, the medium value 123.7 weeks. The Kaplan-Meyer graph analysis showed a significant difference towards the progression-free interval of the IFN PUVA arm (log-rank test; p = 0.0398, 2-sided, Wilcoxen test p = 0.0465). The results are based on 55 documented progressions of 93 patients. The medium progression-free time for the whole group is 63 weeks, for the PUVA arm 53 weeks, and in the combination arm 113 weeks. Based on these findings, we conclude that IFN alfa 2a plus oral photochemotherapy induces a high remission rate with less UVA dose compared to PUVA alone and doubles the progression-free time of CTCL, stages I and II. IFN and PUVA will be the first-line treatment in early CTCL of the EORTC treatment guidelines. No significant financial relationships to disclose.
Utility of D-Dimer LEVEL As a Marker for Differentiation Syndrome, Infection, and Death in ACUTE Promyelocytic Leukemia (APL)
Authors: Catherine R. Caprara, Prachi Kharkhanis, Kathryn Sarah Simon, Stephanie Debragga, Sheldon Bolds, Martha L. Arellano, Anand Jillella, Vamsi Kota
Journal: Blood (2017)
Initial results of a phase III study show safety of HRT and low dose tamoxifen
Authors: B. Bonanni, B. Santillo, D. Serrano, U. Veronesi, M. Rosselli Del Turco, P. Masullo, N. Monti, C. Andreoli, A. Decensi
Journal: Journal of Clinical Oncology (2006)

1009 Background: HRT is beneficial on menopausal disturbancies and decreased bone fracture risk and colorectal cancer (CRC), but increased VTE, cardiovascular events and breast cancer in the WHI trial. However, the WHI characteristics (median age 63.3 yrs, median BMI 28.5, use of oral HRT) diminish generalization of results. The WHI trial shows an increased BC risk, only with oral combined HRT. HRT and tamoxifen (T) was safe in subgroups of two prevention trials. T at low doses showed antiproliferative effects similar to the standard dose, without significant menopausal symptoms and endometrial proliferation. Methods: The HRT+T combination is being investigated in a multicentric, phase III trial in current or de novo HRT users, randomized to either T 5 mg/day or placebo for 5 yrs. The primary endpoint is the reduction of invasive and in situ BC. Results: Of 5,032 women contacted, 1,989 refused, 1,109 were not eligible, and 1,806 were enrolled in 46 centres. Median age is 53 years (33–72). BMI is &lt;20 in 65.7%, &lt;25 in 26.3%, &gt;25 in 8.0%. Current or de novo users are 80.1% and 19.9%. In the former group, 45.9% use oral and 54.1% use TTS. Hysterectomized women are 389. Current users ≤3 years are 48.0%, 3–5 years 12.1%, &gt;5 years 18.8%. 1256 women (74.2%) have at least one follow-up visit. Compared to baseline, most frequent side effects were: hot flashes (42.0% vs 35.0%), night sweating (39.0% vs 29.0%), anxiety/depression (41.0% vs 27.4%), vaginal dryness (29.2% vs 19.3%), headache (32.1% vs 25.1%), fluid retention (24.0% vs 19.0%). “Drop-outs” are 17.3%, of which 11.2% due to adverse events (AE). The 35 AE include: 12 cancers (incl. 7 invasive BC’s, 1 DCIS, 1 CRC), 11 cardiovascular (incl. 1 stroke, 1 AMI, 2 VTE, 1 angina, 2 TIA), 2 gynecologic (uterine polyps). Conclusions: In spite of the current negative scenario for HRT, we have reached over 1,800 women on study. Compliance is acceptable and treatment appears safe. The rate of AE is far lower than the WHI trial, possibly as a result of the different population characteristics. These preliminary findings justify the carry-on of the study in order to reach enough power for the main endpoint and perform secondary evaluations. No significant financial relationships to disclose.
Diabetes but Not Metabolic Syndrome Adversely Impact Survival or Liver Decompensation in Patients with Non-Alcoholic Fatty Liver Related Cirrhosis.
Authors: Luis Bertot, Eduardo Vilar-Gomez, Vincent Wai-Sun Wong, Manuel Romero-Gomez, Rocio Aller-De La Fuente, Grace Lai, Marlen Fernandez, Mohammed Eslam, Jacob George, Leon A. Adams
Journal: Hepatology (2018)
Eosinophil-platelet interactions promote atherosclerosis and stabilize thrombosis with eosinophil extracellular traps
Authors: Charlotte Marx, Julia Novotny, Danby Salbeck, Katie R. Zellner, Leo Nicolai, Kami Pekayvaz, Badr Kilani, Sven Stockhausen, Niklas Bürgener, Danny Kupka, Thomas J. Stocker, Ludwig T. Weckbach, Joachim Pircher, Markus Moser, Michael Joner, Walter Desmet, Tom Adriaenssens, Franz-Josef Neumann, Anthony H. Gerschlick, Jurrien M. ten Berg, Michael Lorenz, Konstantin Stark
Journal: Blood (2019)