tbuckley/cabot-search huggingface dataset:
MBCL-43. PROGNOSTIC FACTORS FOR OVERALL SURVIVAL AFTER RECURRENCE IN CHILDHOOD MEDULLOBLASTOMA
Authors: Sophie Huybrechts, Anaïs Chivet, Christophe Leys, Pascale Varlet, Arnault Tauziede-Espariat, Stéphanie Puget, Léa Guerrini-Rousseau, Jacques Grill, Christelle Dufour
Journal: Neuro-Oncology (2018)

To identify prognostic factors for overall survival (OS) after recurrence in childhood medulloblastoma (MB). PATIENTS AND Consecutive patients with MB treated at Gustave Roussy from 2007 to 2015 were retrospectively reviewed. Central histopathological review and molecular subgrouping are ongoing. Among our cohort of 131 patients, recurrence occurred in 46 children (35%) at median time of 13.5 months (range, 1-88 months). The pattern of recurrence was local in 9 patients, metastatic in 21 and synchronous metastatic and local in 16 patients. One, 3 and 5-year OS from recurrence were 44.7 ± 0.75%, 30.5 ± 0.86% and 25.4 ± 0.85%, respectively. Patients with late recurrence (time from diagnosis until recurrence ≥ 12 months) had a better outcome with a median survival after recurrence of 27 months (95%-CI, 7.67-46.32) compared to those with shorter time to relapse (median of 2 months; 95%-CI, 0.57-3.42). The variables influencing survival after recurrence were time to relapse, histopathological subtype and pattern of relapse/progression. Adjusting for time to relapse, multivariate analysis showed that age at diagnosis (< or > 5 years) was not a significant predictor for OS after recurrence. This study confirmed poor survival of patients with recurrent MB, particularly for those who relapse within 12 months after diagnosis. Yet patients with recurrence beyond 1 year have better outcome and may benefit from new therapies.
EAPH-04. SAFETY AND TOLERABILITY OF CONCOMITANT MULTI-AGENT INTRA-VENTRICULAR CHEMOTHERAPY FOR THE TREATMENT OF RECURRENT CENTRAL NERVOUS SYSTEM (CNS) TUMORS
Authors: Scott Coven, Mohammad Abu Arja, Diana Osorio, Jonathan Finlay
Journal: Neuro-Oncology (2018)

The safety of intra-ventricular or intrathecal monotherapy with topotecan, thiotepa and etoposide has previously been demonstrated in several publications. To our knowledge, the utility of the combination topotecan, thiotepa and etoposide through an intraventricular reservoir as a treatment strategy has never been documented. We describe 8 patients who underwent multi-agent intra-ventricular chemotherapy at Nationwide Children’s Hospital with topotecan, thiotepa and etoposide. The pathological diagnoses included 3 children with medulloblastoma, 2 with ependymoma (1 child, 1 adult), 1 child with AT/RT (atypical teratoid/rhabdoid tumor) and 2 children with atypical malignant tumors with neuraxis dissemination. All intra-ventricular chemotherapy was administered in the setting of relapsed disease concomitant with other forms of systemic chemotherapy. Patients received intra-ventricular chemotherapy from 2 to 84 weeks (median: 8.5 weeks). Four patients died of progressive disease. Of the 4 living patients, one continues on therapy nearly two years from initiation (ependymoma), one has progressive disease (fibromyxoid sarcoma), one has stable disease (primitive neuroepithelial tumor) and one (medulloblastoma) is proceeding to transplant in a minimal disease state. Although we do report several children with myelosuppression, this was in the setting of heavily pre-treated and concurrently-treated patients. Furthermore, we report no headaches, seizures, other neurological toxicities, bleeding or infections from this treatment strategy. We have documented the safety and tolerability of multi-agent intra-ventricular chemotherapy, which can be performed quickly and effectively in the ambulatory clinic. The utilization of multi-agent intra-ventricular chemotherapy could provide an alternative treatment regimen, in combination, for patients with relapsed disease.
Endoscopic ultrasound-guided detection and internal drainage of a closed gastro-cutaneous fistula after bariatric surgery
Authors: Dora Lippai, Alexandru Lupu, Florian Rostain, Jérôme Rivory, Maud Robert, Thierry Ponchon, Mathieu Pioche
Journal: Endoscopy (2018)

Endoscopic drainage of fistulas with plastic stents after bariatric surgery is a minimally invasive technique with high success and low morbidity rates [1] [2]. However, it is sometimes difficult to find or cannulate the internal orifice of the fistula owing to limited maneuverability, a relatively small opening, tortuous trajectory or even spontaneous closure of the orifice. In such cases, endoscopic ultrasound (EUS)-guided puncture can be an option for draining various fluid collections in the abdominal cavity [3] [4], by finding the internal orifice or by creating an additional trajectory to the collection [5].
FOLFIRINOX in pancreatic cancer: A careful review
Authors: E. Una Cidon, P. Alonso
Journal: Annals of Oncology (2018)

Introduction: Pancreatic cancer approach should be multimodal. FOLFIRINOX (5-fluorouracil, oxaliplatin, irinotecan, and leucovorin) has shown effectiveness in the treatment of this disease by increasing response rate with an impact on median survival. Toxicity could be concerning but supportive measures can help significantly. We carried out a retrospective review of pancreatic cancer patients receiving this treatment. We assessed them for response after 3 months of treatment. Methods: All patients diagnosed with metastatic pancreatic cancer were discussed at a multidisciplinary team. Those consider fit enough, were treated with FOLFIRINOX. We assessed primarily the response after three months of treatment and also side-effects. Results: We evaluated 73 patients, 47 female. Median age was 61 (50-69). The most common toxicities grade 3 or higher were gastrointestinal, mainly diarrhoea and nausea/vomiting. 17 patients required admission due to diarrhoea and dehydration. Haematological toxicities such as neutropenia grade 3-4 occurred in 39 patients, 12 of them needed admission due to neutropenic sepsis. Fatigue was also a relevant side-effect present in all the patients, grade 1 in most of them but grade 3 or higher in 43 patients. Dose of chemotherapy was reduced in 48 patients. In 11 of them the reason for a reduction was peripheral neuropathy. 45 patients had a response, 18 stable disease, and the rest progression. Conclusion: FOLFIRINOX as a therapy for metastatic pancreatic adenocarcinoma is a good option providing good supportive measures are in place to reduce the side-effects.
Abstract 89: 17beta-Estradiol-activated Estrogen Receptors Attenuate Cardiac Fibrosis Through Inhibition of Collagen I and III Expression in Female Hearts
Authors: Elke Dworatzek, Shokoufeh Mahmoodzadeh, Christina Westphal, Daniela Fliegner, Vera Regitz-Zagrosek
Journal: Circulation Research (2016)

Objectives: Female pressure-overloaded hearts show less fibrosis compared with males. 17β-Estradiol (E2) attenuates cardiac fibrosis in female mice. Whether this is mediated by direct E2-effects on collagen synthesis is still unknown. Therefore, we investigated the role of E2 and estrogen receptors (ER) on collagen I and III expression and analyzed involved mechanisms. Methods: Female C57BL/6J mice (7 weeks) underwent sham operation, ovariectomy (OVX), OVX with E2-supplementation (390mg E2-containing pellets) or placebo. After 2 weeks, animals underwent transverse aortic constriction (TAC) or sham surgery. Mice were sacrificed after 9 weeks. Collagen amount, collagen I and III protein in left ventricular tissue were detected by Sirius Red and antibody staining, respectively. Gene and protein expression were determined by quantitative Real-Time PCR and Western blot. Adult female rat cardiac fibroblasts were treated with E2 (10 -8 M), vehicle, ERα- and β-agonists (10 -7 M) for 24h or pre-treated with PD98059 for 1h. ER binding to the collagen I and III promoter was analyzed by chromatin immunoprecipitation assays. Findings: In female OVX mice, undergoing TAC surgery, E2-supplementation significantly reduced collagen deposition, collagen I and III mRNA and protein levels in comparison with mice without E2. In female rat cardiac fibroblasts, E2 significantly down-regulated collagen I and III mRNA and protein level. Specific ER-agonist-treatment showed that E2-mediated regulation of collagen I and III expression was mediated via activation of ERα, but not ERβ. Further, upon E2-treatment, ERα was phosphorylated at Ser118, which occurred by E2-induced activation of ERK1/2 signaling. Furthermore, we could show that ERα and ERβ bind to two putative half-palindromic estrogen response elements within the collagen I and III promoter in female cardiac fibroblasts. Conclusion: E2 inhibits cardiac collagen I and III mRNA and protein in female mice under pressure overload. Data from rat female cardiac fibroblasts suggest that this is mediated via E2-activated ERK1/2 signaling and ERα, which binds with ERβ to the collagen I and III promoter. Understanding of how E2/ER attenuate collagen I and III expression in pathological hypertrophy may improve therapy.
NSRG-27. EVOLUTION OF PITUITARY ENDOSURGERY
Authors: Mohamed M Arnaout
Journal: Neuro-Oncology (2018)

Pituitary adenomas constitute about 10-15% of all intracranial tumors. Manifestations are varying from hormonal disturbances to mass effect from compression of the surrounding structures of the skull base to pituitary apoplexy. Surgical management can be achieved via trans-cranial approach or endonasal approaches. HISTORICAL In 1907 Schloffer performed the first pituitary surgery via lateral rhinotomy. This was followed by submucosal resection of septum and endonasal approach then sublabial trans-septal corridor and after that Sublabial Trans-septal Trans-sphenoidal approach. In 1970, the trans-sphenoidal approach has become the preferred approach for pituitary adenomas either sublabial or transnasal. These two approaches were the standard corridor for many years. The development of endoscope allowed its use in such surgeries. At first it was used at the end of the microscopic surgeries to explore residual tumors or blind angles then was used and reported in 1992 by Jankowski et al. who performed endoscopic transnasal transsphenoidal approach, then microscope. This can be termed endoscopic assisted microsurgery. In 1996 Jho et al. described entirely endoscopic transnasal transsphenoidal approach. It was pure endoscopic surgery. Like the new era of new term of micro-neurosurgery, for the last two decades the Endo-neurosurgery is evolving very rapidly. In comparison to surgical microscope better magnification, illumination and close up view provided by the endoscopes has helped in precise delineation of the tumor and has ensured completeness of tumor removal. Extensive knowledge of endoscopic anatomy and training is mandatory starting from observation in operating room, Cadaveric lab., Neurosimulation and finally clinical practice.
QOL-51. NEUROCOGNITIVE SEQUELAE OF CHILDREN TREATED FOR CNS TUMORS: EXPERIENCE FROM THE FIRST SYSTEMATIC EVALUATION IN GREECE
Authors: Natalia Karra, Evangelia Saleptsi, Chrysovalanto-Sofia Karatosidi, Maria Filippidou, Kleoniki Roka, Antonis Kattamis
Journal: Neuro-Oncology (2018)

CNS tumors are the second most common neoplasms in children and primary cause of childhood cancer morbidity. With the increase of 5-year survival rate, the diagnosis of long-term consequences is necessary. Recent studies suggest that childhood CNS tumors are associated with IQ decline and deficits in specific cognitive functions. Factors such as localization, age at diagnosis and therapeutic modalities influence the range and severity of the neuropsychological deficits. This work presents the results of the first systematic evaluation of neuropsychological performance of Greek children with CNS tumors. 72 children underwent neuropsychological testing between September 2015 and December 2017. Forty five children (29 boys, 64%) with mean age of 10.5 (range: 5.3-16.1) years were included in the study. Eighteen (40%) patients had low grade tumors. All patients underwent a comprehensive neuropsychological assessment, covering all domains of cognitive functioning. Impairment was defined as a performance of one standard deviation below the normative mean. Poor neurocognitive performance was found regarding attention (-2sd), speed of processing (-1.5sd), verbal memory (-2sd), learning (-1.5sd) and executive functions (-2sd). Despite the abovementioned deficits, intellectual efficiency was relatively preserved and fell within low average levels (>16%ile). Our results are in line with previous reports suggesting that children who have been treated for CNS tumors present with a wide range of long-term effects on cognitive functioning. Longer follow-up and expansion of the sample may give for further insights on the factors associated with poor neurocognitive outcome and allow appropriate intervention for optimal outcome.
Recurrent <i>RARB</i> Translocations in Acute Promyelocytic Leukemia Lacking <i>RARA</i> Translocation
Authors: Tomoo Osumi, Shin-ichi Tsujimoto, Moe Tamura, Meri Uchiyama, Kazuhiko Nakabayashi, Kohji Okamura, Masanori Yoshida, Daisuke Tomizawa, Akihiro Watanabe, Hiroyuki Takahashi, Tsukasa Hori, Shohei Yamamoto, Kazuko Hamamoto, Masahiro Migita, Hiroko Ogata-Kawata, Toru Uchiyama, Hiroe Kizawa, Hitomi Ueno-Yokohata, Ryota Shirai, Masafumi Seki, Kentaro Ohki, Junko Takita, Takeshi Inukai, Seishi Ogawa, Toshio Kitamura, Kimikazu Matsumoto, Kenichiro Hata, Nobutaka Kiyokawa, Susumu Goyama, Motohiro Kato
Journal: Cancer Research (2018)

Abstract Translocations of retinoic acid receptor-α (RARA), typically PML–RARA, are a genetic hallmark of acute promyelocytic leukemia (APL). However, because a small fraction of APL lack translocations of RARA, we focused here on APL cases without RARA translocation to elucidate the molecular etiology of RARA-negative APL. We performed whole-genome sequencing, PCR, and FISH for five APL cases without RARA translocations. Four of five RARA-negative APL cases had translocations involving retinoic acid receptor-β (RARB) translocations, and TBL1XR1–RARB was identified as an in-frame fusion in three cases; one case had an RARB rearrangement detected by FISH, although the partner gene could not be identified. When transduced in cell lines, TBL1XR1–RARB homodimerized and diminished transcriptional activity for the retinoic acid receptor pathway in a dominant-negative manner. TBL1XR1–RARB enhanced the replating capacity of mouse bone marrow cells and inhibited myeloid maturation of human cord blood cells as PML–RARA did. However, the response of APL with RARB translocation to retinoids was attenuated compared with that of PML–RARA, an observation in line with the clinical resistance of RARB-positive APL to ATRA. Our results demonstrate that the majority of RARA-negative APL have RARB translocations, thereby forming a novel, distinct subgroup of APL. TBL1XR1–RARB as an oncogenic protein exerts effects similar to those of PML–RARA, underpinning the importance of retinoic acid pathway alterations in the pathogenesis of APL. Significance: These findings report a novel and distinct genetic subtype of acute promyelocytic leukemia (APL) by illustrating that the majority of APL without RARA translocations harbor RARB translocations. Cancer Res; 78(16); 4452–8. ©2018 AACR.
HGG-12. PRIMARY BITHALAMIC GLIOMA WITH EGFR MUTATION: A RARE CASE REPORT
Authors: Reuben Antony, David Solomon, Lee-Way Jin, Arie Perry, Sabine Mueller, Marike Zwienenberg-Lee, Arzu Ozturk
Journal: Neuro-Oncology (2018)

Primary Bilateral Thalamic Gliomas (PBTG) are rare in children. They usually have high grade infiltrative histology and absence of the histone H3 K27M mutation. Most affected patients have a poor outcome regardless of therapy. We report a 12 year old boy diagnosed with a PBTG harboring an EGFR exon 20 insertion mutation commonly seen in lung adenocarcinoma but very rare in childhood glioma. CASE Our patient presented to an outside hospital (OSH) with a 4 day history of worsening bifrontal headaches. CT brain demonstrated an intracranial mass so patient was transferred to our center. MRI brain performed at admission demonstrated large non-enhancing bithalamic masses with mass effect on the third ventricle/Foramina of Monro. Biopsy of the left thalamic mass followed by immunohistochemistry and genomic analysis (targeted next-generation sequencing) resulted in the following integrated diagnosis - high grade (WHO Grade 3) infiltrating glioma, IDH and H3-wildtype, hemizygous TP53 frameshift mutation, focal homozygous deletion of CDKN2A / CDKN2B tumor suppressor genes, and a small in-frame insertion (exon 20) of the EGFR oncogene. The presence of an EGFR exon 20 insertion mutation affecting the intracellular tyrosine kinase domain is exceptional in this tumor. No pathogenic alterations in BRAF, NF1, FGFR1, MET, PTEN, PDGFRA, IDH1/IDH2, H3F3A, HIST1H3B, ATRX, or TERT genes were identified. He completed chemoradiotherapy (irradiation/temozolomide/bevacizumab) and is currently receiving maintenance therapy with bevacizumab, temozolomide, and a CNS penetrating 3rd generation EGFR pathway inhibitor osimertinib. Interrogating PBTGs for EGFR mutations may reveal a therapeutic target and improve the outcome of affected patients.
Efficacy and safety of pegylated human IL-10 (AM0010) in combination with an anti-PD-1 in renal cell cancer.
Authors: Aung Naing, Jeffrey R. Infante, Deborah Jean Lee Wong, Wolfgang Michael Korn, Raid Aljumaily, Kyriakos P. Papadopoulos, Karen A. Autio, Shubham Pant, Todd Michael Bauer, Alexandra Drakaki, Naval Guastad Daver, Annie Hung, Peter Van Vlasselaer, Gail Linda Brown, Martin Oft, Nizar M. Tannir
Journal: Journal of Clinical Oncology (2017)

4567 Background: IL-10 has anti-inflammatory activity and stimulates the cytotoxicity and proliferation of CD8+ T cells at higher concentrations. IL-10 receptors and PD1 are expressed on activated CD8 T cells, providing a rationale for combining AM0010 and an anti-PD1. The efficacy and safety profile for AM0010 alone was established in poor to intermediate risk RCC pts treated in 3 rd LOT. Objective responses were observed in 4 of 15 pts with RCC. In the dose escalation of AM0010 plus pembrolizumab, 4 of 8 patients had an objective response. The mPFS was 16.7 months and the mOS has not been reached, median follow up (mFU) is 19.3 mo. Methods: In this Phase 1b, 29 pts. with metastatic RCC were enrolled until Nov. 18 2016 on AM0010 (10 ug/kg daily SC) and nivolumab (3mg/kg, q2wk IV). 2 had favorable, 20 had intermediate and 4 had poor IMDC risk (3 were not available). Pts. had a median of 1 prior therapy (range 1-3). All pts. had received a VEGFR-TKI. Tumor responses were assessed with irRC. Immune responses were evaluated by serum cytokines, activation of blood derived T cells and peripheral T cell clonality. Results: AMO010 plus nivolumab was well tolerated. TrAEs were reversible. There were no autoimmune colitis, pneumonitis, or endocrine disorders. 14 patients had at least 1 G3/4 TrAE, including anemia (9), thrombocytopenia (5), hypertriglyceridaemia (4). 2 pts had a reversible cytokine release syndrome with splenomegaly and increased immune mediated red blood cell phagocytosis most likely precipitated by T-cell activation, as both pts had tumor responses. As of Jan 31 2017, partial responses (PR) were observed in 8 of 26 evaluable pts (31%). An additional 13 of 26 pts had stable disease (41%), 7 pts had tumor reductions of more than 30%. The mPFS and mOS has not been reached with a mFU of 5.2 mo. (range 0.3-10.3). AM0010 + anti-PD1 increased Th1 cytokines in the serum while decreasing TGFb, an expansion of proliferating PD1+ Lag3+ activated CD8 T cells and de-novo oligoclonal expansion of T cell clones in the blood. Conclusions: AM0010 in combination with nivolumab is well-tolerated in RCC pts. The efficacy and the observed CD8 T cell activation is promising and encourages the continued study of AM0010 in combination with nivolumab. Clinical trial information: NCT02009449.
MicroRNAs and CDH1 regulation in intestinal-type gastric cancer
Authors: C. Molinari, T. Rossi, R. Abou Khouzam, G. Ranzani, G. Tedaldi, P. Ulivi, P. Morgagni, L. Saragoni, M. Monti, D. Calistri
Journal: Annals of Oncology (2018)

Introduction: Gastric cancer (GC) remains a major source of cancer morbidity and mortality worldwide. The most commonly accepted histologic classification of this disease separates it into two main subtypes: intestinal (IGC) and diffuse (DGC). The cadherin family is a cell adhesion-related protein family largely implicated in carcinogenesis of both histotypes, with the best-known member being E-cadherin. This calcium-dependent transmembrane adhesion protein is encoded by CDH1 tumor suppressor gene. While complete loss of E-cadherin is predominant in DGC, more subtle factors can be involved in its modulation in IGC, in which some level of protein is often retained. Such factors include miRNAs that play a role in gene expression dosage either directly by interacting with the CDH1 transcript, or indirectly by acting on genes that are part of its regulatory network. Aim of the study was to evaluate the levels of specific miRNAs involved in the regulation of CDH1 expression in IGC. Methods: Fresh-frozen paired normal and cancer tissue samples were obtained from 40 patients diagnosed with IGC. An in silico and literature based approach was performed to determine the miRNAs most likely targeting CDH1 in GC. In case of an indirect effect on CDH1, the direct miRNA targets were noted. Expression analysis was carried out by using a custom-made RT pool containing primers for the miRNAs of interest and the TaqMan microRNA RT Kit. This was followed by qPCR reactions in miRNA custom-made 96-well plates and quantification by the 2-ΔCt method with RNU6 as a reference. CDH1 expression levels were quantified by two step reverse transcription dPCR with GAPDH as an endogenous control. Results: The combined in silico and literature-search based approach gave rise to a list of 14 miRNAs possibly involved in the regulation of CDH1 expression in GC (miR-506, miR-217, miR-199a, miR-153, miR-544a, miR-34c, miR-141, miR-429, miR-101, miR-200a, miR-200b, miR-200c, miR-26b, miR-23a). Tumor and normal paired samples from 17 patients have been analyzed so far. At the end of the qPCR reactions, 8 miRNAs could be successfully quantified (miR-141, miR-429, miR-200a, miR-200b, miR-200c, miR-101, miR-26b and miR-23a); among those miR-101 (p = 0.00236) and miR-26b (p = 0.001623) were found to be significantly lower in tumors compared to normal tissue, while miR-200c showed borderline significance (p = 0.05373). With respect to CDH1, it was similarly found to be significantly less in tumor than normal tissue (p = 0.01). Meanwhile, no significant correlations were found between miRNAs and CDH1 expression levels. Conclusion: Based on our preliminary results both miR-26 and miR-101 seem to contribute to IGC carcinogenesis. To further investigate whether they act by perturbing E-cadherin-mediated signaling and cell-cell adhesion we are planning to analyze a bigger case series.