tbuckley/cabot-search huggingface dataset:
P14.90 Interleukin 6 is a useful marker for pseudotumoral inflammatory CNS lesions suspicious of lymphoma
Authors: A Ungureanu, M Costopoulos, T Parratte, A Brinet, H Durand, C Gaultier, T Postert, R Hurstel, I Alamome, F Sellal, M Le Garff-Tavernier, G Ahle
Journal: Neuro-Oncology (2019)

Abstract BACKGROUND Interleukin (IL)-6 is a dual pro and anti-inflammatory cytokine and its presence in the cerebrospinal fluid (CSF) is considered as a marker of central nervous system (CNS) inflammation. Our aim was to analyze the diagnostic significance of CSF IL-6 levels among various CNS pseudotumoral inflammatory lesions (PIL) and primary CNS lymphoma (PCNSL). MATERIAL AND METHODS We retrospectively analyzed the CSF IL-6 concentrations in 43 patients with a differential diagnosis of PCNSL. Finally, 28 patients were positively diagnosed with PCNSL and 15 with other inflammatory CNS disorders. We verified the results with CSF IL-10, a biomarker for PCNSL. IL concentrations were measured by flow cytometry using the cytometric bead array (CBA) technique (BD Biosciences) with a detection limit set at 2.5 pg/ml. RESULTS In the PCNSL group, the median CSF IL-6 concentration was 8 pg/ml, interquartile range (IQR) 5 - 18.5. For the patients with other PIL the median concentration was of 70 pg/ml, IQR 5 - 1368. A group comparison disclosed significantly higher CSF IL-6 levels in patients with PIL compared to the group with PCNSL (p=0.032). Moreover, IL-6 was correlated with CSF cell count for the whole cohort (r=0.45, p=0.002), as well as for the PIL group (r=0.56, p=0.028), but not for the PCNSL group (r=0.3, p=0.13). We found significantly higher CSF IL-10 levels in patients with PCNSL compared to the group with other CNS inflammatory lesions (p&lt;0.001). CONCLUSION Our study suggests that CSF IL-6 levels could represent, in addition to CSF IL-10, a useful biomarker in the diagnosis of CNS PIL that may mimic PCNSL.
P14.87 Leptomeningeal dissemination in high grade glioma: Correlation of MRI, cytology and standard CSF indices
Authors: H Durand, F Lamy, T Parratte, A Brinet, A Blain, F Lamy, C Gaultier, L Droy-Dupré, S Leblanc, H Oesterlé, S Olteanu, D Atlani, J Voirin, K Mokhtari, G Ahle
Journal: Neuro-Oncology (2019)

Abstract BACKGROUND Only few studies report the incidence of leptomeningeal dissemination (LMD) in patients with high grade glioma (HGG), although LMD is not a rare condition of recurrence. We aimed to describe the diagnostic features and treatment modalities in a series of patients treated for HGG in our institution. METHODS Review of clinical presentation, radiological features and CSF analysis in a case series. RESULTS 17 patients from our institution were diagnosed with LMD. The diagnosis of LMD was based on magnetic resonance image and/or cerebrospinal fluid (CSF) analysis. The spectrum of clinical presentation was broad, mainly intracranial hypertension, impaired general condition, pain, worsening of pre-existing symptoms, and epileptic seizures. Median time from onset of clinical deterioration to diagnosis of LMD was 3 weeks (0–16). Leptomeningial involvement was reported in 6/17 at initial MRI reading, whereas reassessment with careful comparison to previous MRI showed signs of LMD in all patients. CSF analysis revealed pleocytosis (11/17), high proteinorrachia (13/17), elevated lactate levels (15/16), low glucose levels (5/17), and increased CSF pressure (5/9). Nevertheless, diagnostic accuracy of initial CSF cytological analysis was low (2/17). A reassessment of the specimen by an experienced neuropathologist disclosed 1 additional positive and 1 additional suspect cytology. After diagnosis of LMD, salvage treatments comprised Bevacizumab, Lomustine, Fotemustine, liposomal cytarabine and best supportive care. The median overall survival after the diagnosis was 3 months. DISCUSSION AND CONCLUSIONS LMD in HGG is not a rare condition of recurrence, and its outcome is poor. It remains a diagnostic challenge, as it may be overlooked on MRI follow-up at its early stage. In case of clinical progression with no overt cause reported on MRI, we recommend careful second MRI reading. In case of doubt lumbar puncture should be performed in order to prove LMD and eliminate infection (i.e. HSV). Upon standard CSF indices, elevated lactate levels should give rise to the suspicion of LMD. Cytological CSF analysis seems to be of low diagnostic yield: This may be improved by faster processing after sampling and by standardized workup including staining with IDH, GFAP and Olig2.
Inhaled GM-CSF for Pulmonary Alveolar Proteinosis
Authors: Ryushi Tazawa, Takahiro Ueda, Mitsuhiro Abe, Koichiro Tatsumi, Ryosuke Eda, Shotaro Kondoh, Konosuke Morimoto, Takeshi Tanaka, Etsuro Yamaguchi, Ayumu Takahashi, Miku Oda, Haruyuki Ishii, Shinyu Izumi, Haruhito Sugiyama, Atsushi Nakagawa, Keisuke Tomii, Masaru Suzuki, Satoshi Konno, Shinya Ohkouchi, Naoki Tode, Tomohiro Handa, Toyohiro Hirai, Yoshikazu Inoue, Toru Arai, Katsuaki Asakawa, Takuro Sakagami, Atsushi Hashimoto, Takahiro Tanaka, Toshinori Takada, Ayako Mikami, Nobutaka Kitamura, Koh Nakata
Journal: New England Journal of Medicine (2019)

Pulmonary alveolar proteinosis is a disease characterized by abnormal accumulation of surfactant in the alveoli. Most cases are autoimmune and are associated with an autoantibody against granulocyte–macrophage colony-stimulating factor (GM-CSF) that prevents clearing of pulmonary surfactant by alveolar macrophages. An open-label, phase 2 study showed some therapeutic efficacy of inhaled recombinant human GM-CSF in patients with severe pulmonary alveolar proteinosis; however, the efficacy in patients with mild-to-moderate disease remains unclear.
“Some exercise is good, more is better,” say medical chiefs in new guidance
Authors: Gareth Iacobucci
Journal: BMJ (2019)

New mothers should undertake a moderate amount of exercise to help them regain strength, ease back pain, and reduce the risk of gestational diabetes, the UK’s four chief medical officers have advised.

The recommendation is included in updated physical activity guidelines, which include advice on safe levels of activity for pregnant and postpartum women. The guidelines update the existing 2011 physical activity guidance for all age groups, drawing on the latest evidence available.

The updated guidelines emphasise the importance of building strength and balance, as well as cardiovascular exercise for adults. Adults aged 19-64 are advised to undertake strength based activities—such as …
P14.28 First report on the combination of axitinib and Tumor Treating Fields (TTFields) in three patients with recurrent glioblastoma
Authors: A F Keßler, J Weiland, T Linsenmann, R Ernestus, C Hagemann, M Löhr
Journal: Neuro-Oncology (2019)

Abstract BACKGROUND Adding Tumor Treating Fields (TTFields) to first-line therapy in glioblastoma (GBM) demonstrated significantly improved survival in the EF-14 trial. Furthermore, in a post-hoc analysis of the EF-14 trial, median overall survival increased significantly upon recurrence (rGBM) for patients treated with bevacizumab (Bev) and TTFields compared to Bev monotherapy. Axitinib (Axi) is an orally available tyrosine kinase inhibitor which is approved for the treatment of metastatic renal cell carcinoma. It has a high affinity and specificity for vascular endothelial growth factor receptors, thereby acting similar to Bev. In phase 2 trials, Axi improved response rate and progression free survival in rGBM patients compared to historical controls with a manageable toxicity profile. We report on three rGBM patients treated with TTFields and Axi (AxiTTFields). METHODS A 53-year-old male patient (#1) presented with a multifocal and consistently progressing GBM after initial surgery, radiochemotherapy (RCT) and after 4 cycles of temozolomide (TMZ), combined with TTFields. To meet the urgent need of an alternative treatment, Axi (5mg twice a day) was added to the treatment regimen. In a 46-year-old male patient (#2), an early progress occurred after surgery, RCT and 3 cycles of TMZ combined with TTFields. Similarly to #1, Axi was added to the treatment regimen. In a 61-year-old male patient (#3) with a rGBM after surgery and RCT at the time of the 6th cycle of TMZ, TTFields therapy was initiated at recurrence and treatment regimen was adapted to AxiTTFields. RESULTS In these three patients, AxiTTFields was safe and feasible. #1 and #2 were on AxiTTFields therapy for more than 8 months, presenting an improved neurological status with a partial response in the MRI 3 months initiating the combined treatment of AxiTTFields. #3 declined in his neurological status without any change in the MRI monitoring and died 2.4 months after initiating AxiTTFields. Although, Axi as well as TTFields may cause skin irritations, none were observed in this case series. With an average of 77 % in these three patients, the TTFields usage rate was above the independent prognostic threshold of 75 %, underlining the feasibility of this approach. There were no additional adverse events due to the combined therapy of AxiTTFields. CONCLUSION In summary, AxiTTFields was feasible and safe in three rGBM patients. As the addition of Axi to TTFields therapy is a promising approach, we plan to investigate the safety and feasibility of this combination in a pilot trial. Further studies might explore effects on outcome and survival of AxiTTFields in rGBM.
Dealing with emotional states during cancer diagnosis and treatment by using cognitive strategies in oncology patients: Comparison to noncancer population.
Authors: Anna Kieszkowska-Grudny, Monika Rucinska, Karolina Osowiecka
Journal: Journal of Clinical Oncology (2019)

e23184 Background: Diagnosis of cancer is perceived by individuals as a life-threatening event. Patients (pts) experience a great distress, as well as a various emotions and apply diverse cognitive strategies to deal with them during cancer diagnosis and its treatment. State of mind can help in emotions management and could be supportive or destructive during treatment.Employing adaptive strategies may help them to cope better this specific traumatic event and help doctors to get higher compliance with their pts.Therefore, it is important first to recognize these strategies and then arrange personalized psychological support for them in cooperation with oncologist. Methods: 197 individuals were included into the study between 11.2017 and 12.2018: 115 cancer pts ( Me= 62years) and 82 healthy subjects ( Me= 45years). All subjects filled out: Cognitive-Emotional Regulation Questionnaire(with 4 non-adaptive strategies (NAS)–self-blame, blaming others, catastrophizing, rumination and 4 adaptive strategies (AS)–acceptance, refocus on planning, putting into perspective, attention to something positive), and demographic data. Statistical analyses were based on t-Students test and linear correlation (significance level: p &lt; .05). Results: Significant differences were observed between cancer patients and healthy group in all types of cognitive strategies. Cancer pts tend to catastrophize more frequently ( p &lt; .01) and employed planning strategies less often ( p &lt; .001), but generally had more AS( p &lt; .01), especially attention to sth positive and acceptance ( p &lt; .001). In cancer group NAS, especially catastrophizing ( p &lt; .05) and rumination ( p &lt; .001) correlate negatively with education and place of living, which means that less educated pts and living in the countryside had more NAS. In contrast, cancer pts living in cities used more AS( p = .001), mainly attention to sth positive, refocus on planning ( p &lt; .01) and putting into perspective ( p &lt; .001). The older pts less often applied focus-on-planning strategy ( p &lt; .01). Conclusions: Cancer pts rarely used planning strategies and tend to develop an extremely negative future vision, but generally had more AS to deal with traumatic event then healthy population. More attention should be given to pts with cancer who are older, live in in the countryside and are less educated.
P11.03 Next generation sequencing-identified IDH-1, ATRX, TP53 mutation and MYCN amplification in glioblastoma with primitive neuroectodermal tumor-like feature and extensive subarachnoid spread: a case report
Authors: K Lee, C Gheeyoung
Journal: Neuro-Oncology (2019)

Abstract BACKGROUND In recent years, there have been numerous molecular studies in the glioblastoma. With regard to glioblastoma showing primarily extensive subarachnoid spreading, however, the pathogenesis remains to be determined due to its low incidence. Present report is a rare case of glioblastoma with primitive neuroectodermal tumor (PNET)-like feature, showing extensive subarachnoid spread, as well as the distinguishing result of its molecular analysis using next generation sequencing (NGS). DESCRIPTION A 37-year-old male presented with a new onset, severe headache. Magnetic resonance imaging (MRI) test revealed a diffuse infiltrative mass in the right frontal lobe. The tumor was also spread broadly in subarachnoid space. The patient underwent craniotomy and tumorectomy. Microscopically, glioblastoma showed PNET-like feature. Tumor cells had high nuclear/cytoplasmic ratios, oval, slightly elongated or angulated hyperchromatic nuclei, markedly increased mitotic activity, and obvious apoptotic bodies. Immunohistochemical analysis showed partly positivity of GFAP. Also this tumor demonstrated CD56 and synaptophysin immunoreactivity. IDH-1 immunohistochemistry was negative, which initially led to the diagnosis of glioblastoma, IDH wild-type. However, IDH-1 (p.Arg132His) mutation was found in subsequent NGS test. Additionally, two frame shift genetic alteration was found including ATRX (p.Tyr2208fs) and TP53 (p.Pro301fs). Interestingly, also MYCN (2p24.3) amplification was identified by both NGS and fluorescence in situ hybridization (FISH) test. Estimated MYCN copy number was 18. Despite the post-operative therapy including temozolomide and radiotherapy was performed, the tumor aggressively progressed and the patient expired nine months after the first symptom onset. CONCLUSION Although there have been several previous reports of MYCN amplification in glioblastoma with PNET-like feature, this is the first case report which finding in IDH-mutant type. IDH-1 mutation and younger age are usually associated with a better prognosis in glioblastoma. However, this case may suggest that when MYCN amplification coexists in IDH-mutant type, the tumor behavior could be contrarily aggressive.
c-kit: Identification of co-regulated genes by gene expression profiling and clinical relevance of two breast cancer subtypes with stem cell like features
Authors: A. Rody, U. Holtrich, V. Müller, R. Gaetje, R. Diallo, M. Gehrmann, G. Von Minckwitz, K. Engels, T. Karn, M. Kaufmann
Journal: Journal of Clinical Oncology (2006)

622 Background: Expression of the proto-oncogene c-kit has been found in malignant tissue including a subset of breast cancers. c-Kit is also expressed in normal breast tissue and several authors found a loss of c-kit expression in breast carcinoma suggesting it might be involved in the growth control of mammary epithelium. Until now, only a few markers were described to be co-regulated with c-kit. To elucidate the possible role of c-kit in malignant transformation, we analyzed gene expression data of breast cancer patients. Methods: Tumor tissue of n=171 breast cancer patients were analyzed by gene expression profiling using Affymetrix Hg U133 Arrays (22,500 genes) and bioinformatic analyses. Tumor samples with high stromal and low epithelial cell content by gene expression profiling were excluded for further analysis. Validation was performed with n=100 independent samples. Results: A total of 10.5% of the tumors showed strong c-kit expression (2.5 fold above median). A careful dissection of global expression data revealed strong correlations of c-kit with the expression of a large cluster of genes containing several for whom c-kit coexpression was already described (HER1, CK-5/-17, PDGFR) as well as several members of the wnt signalling pathway, providing a possible novel link to mammary epithelial differentiation. Analysis of n=171 breast cancer samples according to this gene set allows the identification of putative “stem cell like” tumors (SCL) characterized by expression of several known stem cell markers. Surprisingly, a tight link of ER status and proliferation is restricted only to these SCL tumors but lost among non-SCL tumors. The clinical implications of our findings will be presented. Conclusions: For the first time these data bring together the description of two breast cancer subtypes identified by gene expression profiling with the actual stem cell model of the development of breast cancer. No significant financial relationships to disclose.
The phase Ib result of the safety and efficacy of lenvatinib (lenv) plus eribulin (eri) in advanced adipocytic sarcoma (LPS) and leiomyosarcoma (LMS): LEADER study (NCT03526679).
Authors: Tom Wei-Wu Chen, Ruey-Long Hong, Chueh-Chuan Yen, San-Chi Chen, Jhe-Cyuan Guo, Meng-Chi Hsu, Ting-Fang Kung
Journal: Journal of Clinical Oncology (2019)

e22524 Background: Eri, although approved for advanced LPS, has limited activity in terms of tumor shrinkage. Anti-angiogenic agents have shown to increase tumor response in certain cancer types. This study aims to understand the safety, optimal dose, and efficacy of the combination of lenv, a multi-kinase anti-angiogenic inhibitor, and eri in LMS and LPS. Methods: Advanced LMS and LPS with no more than 2 lines of systemic chemotherapy were eligible. The starting dose was lenv 18mg/day daily and eri 1.1mg/m2 D1, D8 in a 21-day cycle. The primary endpoint of the phase Ib part was to assess the dose-limiting toxicity (DLT) in the first 21 days and to determine the recommended phase II dose (RP2D). A rule-based (≤ 33% DLT in first 6 pts) design was implemented in the phase Ib part. Results: From 2018 Jul 24 to 2019 Jan 8, a total of 6 pts (4 LMS, 1 dedifferentiated LPS, 1 myxoid LPS) were enrolled. The median age was 56 (range 30-70), female: male 3:3. Only 1 pt had a DLT, which was &lt; 75% of the planned dosage. Within all (27) cycles, common grade (gr) 3 or higher adverse events (AE) included hypertension (HTN, n = 4), hand-foot syndrome (HFS, n = 3), and neutropenia (n = 4). However, 4 pts had late-onset gr3 or multiple coexisting gr2 AEs that necessitated dose reduction(s) (dr) for lenv (7 dr) or eri (2 dr) after the DLT assessment period (see table). The median time to 14 mg/day, 10mg/day of lenv, and eri 0.7mg/m2 was 22, 28 (after starting lenv 14mg/day), and 69 days, respectively. In terms of preliminary anti-tumor activity, 5 (83%) pts had target lesion shrinkage and 2 (33%) reached PR (1 confirmed) as best response according to RECIST 1.1. Conclusions: Late-onset AEs after cycle 1 leading to dose reduction was notable for lenv + eri and the RP2D was thus determined at a lower starting dose of lenv 14mg/day and eri 1.1mg/m2. The preliminary tumor response was also promising. Efficacy and safety of lenv + eri for LMS and LPS will continue to be explored in phase II study. Clinical trial information: NCT03526679. [Table: see text]
Risk of tumor-related death in stage I-III colon cance based on gender and tumor location.
Authors: Robert D. Ladner, Michael Kahn, Dongyun Yang, Sebastian Stintzing, Wu Zhang, Takeru Wakatsuki, Yan Ning, Nico Benjamin Volz, Joseph Ethan Li, Melissa Janae Labonte, Peter M. D. Wilson, Adel Kardosh, Heinz-Josef Lenz
Journal: Journal of Clinical Oncology (2013)

e14538 Background: Survival of metastatic colon cancer has recently been linked to gender and location of the primary. Data on these factors in the stage I-III is still sparse. We aimed to demonstrate the influence of gender and tumor location of tumor related survival, using SEER database. Methods: 288,640 patients diagnosed with stage I-III colon cancer during 1988 through 2009 identified from SEER database were included in this study. Cox proportional hazards models were used to evaluate the effects of tumor site (left vs right-sided colon) on colorectal cancer specific survival. Age, race, T stage, N stage, histology (adenocarcinoma, mucinous tumor), grading, numbers of lymph nodes resected and type of surgery were used as covariates. Results: A total of 85,131 (stage I), 110,667 (stage II) and 92,842 (stage III) patients were identified to have data on all the factors to be looked at. In the total population female gender was statistically significant for longer TSS for all three stages (HR 0.82; HR 0.86 and HR 0.89). Furthermore, in UICC I and UICC III left side was favorable (HR 0.82 and HR 0.91) but in stage II, right sided colon cancer patients had a longer TSS (HR 1.2 for left side). This was independent of gender. Conclusions: Different prognoses of right versus left colon cancer reflect different biology. Furthermore the influence of gender points to an estrogen effect in female patients. As there is emerging knowledge about the differences in right versus left colon cancer biology, the modulating effect of SMAD4 on estrogen driven TGFß signaling might be one explanation to those differences.
Second primary melanomas in a cohort of 977 melanoma patients within the first 5 years of monitoring
Authors: Aimilios Lallas, Zoe Apalla, Athanassios Kyrgidis, Chryssoula Papageorgiou, Ioannis Boukovinas, Mattheos Bobos, George Efthimiopoulos, Christina Nikolaidou, Andreas Moutsoudis, Theodosia Gkentsidi, Konstantinos Lallas, Elizabeth Lazaridou, Elena Sotiriou, Efstratios Vakirlis, Dimitrios Ioannides
Journal: Journal of the American Academy of Dermatology (2019)
OS6.2 Loss of CYP46A1 directs altered cholesterol homeostasis and opens therapeutic opportunities for glioblastoma
Authors: M Han, S Wang, X Li, J Wang, R Bjerkvig
Journal: Neuro-Oncology (2019)

Abstract BACKGROUND Dysregulated cholesterol metabolism is a hallmark of many cancers, including glioblastoma (GBM), but its role in disease progression is not well understood. Here, we identified cholesterol 24-hydroxylase (CYP46A1), a brain-specific enzyme responsible for elimination of cholesterol through conversion of cholesterol to 24(S)-hydroxycholesterol (24OHC), as one of the most dramatically dysregulated cholesterol metabolism genes in GBM. MATERIAL AND METHODS Molecular and clinical data was obtained from publicly genomic databases. Immunohistochemistry was applied to assess protein levels of CYP46A1 in primary GBM samples. Lentiviral constructs expressing CYP46A1 were transduced into LN229, LN18 and primary GBM GSCs for functional assays carried out in vitro and in vivo in an orthotopic xenograft model. RNA-seq was performed to identify downstream targets of 24OHC. RESULTS CYP46A1 was significantly decreased in GBM samples compared to normal brain tissue. Reduced CYP46A1 expression was associated with increasing tumour grade and poor prognosis in GBM patients. Ectopic expression of CYP46A1 suppressed cell proliferation and in vivo tumour growth by increasing 24OHC levels. Treatment of GBM cells with 24OHC suppressed tumour growth through regulation of LXR and SREBP signalling. Efavirenz (EFV), an activator of CYP46A1 with BBB penetration, inhibited GBM growth in vivo. CONCLUSION Our findings demonstrate that CYP46A1 is a critical regulator of cellular cholesterol in GBM and that the CYP46A1/24OHC axis is a potential therapeutic target.