tbuckley/cabot-search huggingface dataset:
The prognostic role of microsatellite status, tumor mutational burden and protein expression in CRC
Authors: J. Lam, Y. Kim, F. Cecchi, S. Woo, A. Chambers, I. Tan, C. Chua Wei Ling, K. Si-Lin, L. Wei Qiang, T. Lim Kiat Hon, S. Anders Martin Jacobsen, T. Hembrough
Journal: Annals of Oncology (2018)

Introduction: Comprehensive molecular profiling of CRC can inform treatment decisions by identifying patient subgroups at varying risks of death. Microsatellite instability (MSI) is prognostic in CRC and is used to select patients for immunotherapy. High tumor mutational burden (TMB) is associated with genomic instability and is prognostic in melanoma. Expression of p16 protein is prognostic in many tumor types. We used proteomic and genomic profiling to measure MSI, TMB and p16 in CRC tumors and to assess associations with patient survival. The global proteome data was also used to identify potentially prognostic protein biomarkers. Methods: In archived clinical samples of CRC, 76 proteins were quantitated with mass spectrometry-based proteomics. MSI was measured by whole genome sequencing; unstable loci were quantified in tumor and normal samples. Cutoffs were derived via ROC analysis: high TMB was defined as > 4.5 somatic mutations per megabase; p16 as > 108 amol/ug. Patients were grouped by microsatellite status (MSI vs. microsatellite stable [MSS]), TMB (high vs. low), and p16 protein expression level. Survival curves were compared with the Mantel-Cox log-rank test. Results: Of 145 samples, 39 (27%) had high TMB and 29 (20%) had MSI. Patients with MSI tumors had longer OS than patients with MSS tumors (HR: 0.096; p = 0.003). Similarly, patients with high TMB had longer OS than those with low TMB (HR: 0.076; p < 0.001). High p16 expression was prognostic of poor survival (HR: 2.874; p = 0.019). Among patients with MSS tumors or low TMB, those with low p16 levels had longer OS than patients with high p16 (HR: 0.257; p = 0.002 and HR: 0.249; p = 0.002, for MSS and low TMB, respectively). A combination of MSS, low TMB, and low p16 also differentiated between long and short survivors (HR: 0.249; p = 0.002). These associations remained after adjustment for tumor sidedness. Analysis of proteome expression profiles of individual CRC biopsies (n = 80) detected 5021 quantifiable proteins. Among these, we identified a list of proteins that separated CRC patients by CMS subtypes. Further analyses of clinical correlates will be presented Conclusion: A combination of MSS, low TMB and low p16 expression characterized a subset of patients with longer survival. This is important because patients with MSS tumors have limited treatment options but may respond to CDK4/6 inhibitors due to low p16 expression. Molecular profiling of CRC may identify patient subgroups with a relatively poor prognosis who could benefit from personalized therapy.
A Phase II multi institutional study of nivolumab in patients with advanced refractory biliary tract cancers (BTC)
Authors: R. Kim, D. Kim, O. Alese, D. Li, B. El-Rayes, N. Shah, M. Schell, J. Zhou, V. Chung
Journal: Annals of Oncology (2018)

Introduction: Biliary tract cancers (BTC) typically include intra and extrahepatic cholangiocarcinoma and cancers of the gallbladder. There is no established second line option for patients with advanced BTC who have failed one prior systemic therapy. There are pre-clinical and small series of clinical data which supports the usage of immune modulatory agents in BTC. Therefore we propose to evaluate the anti-PD1 agent nivolumab in advanced, refractory BTC. Methods: Pts with histologically proven BTC who progressed on at least one line of systemic therapy received nivolumab 240mg IV q2weeks for 16 weeks and then 480 mg IV every 4 weeks until disease progression or unacceptable toxicity The Simon two staged design was used to assess objective response rate (ORR) by RECIST 1.1 every 8 weeks as a primary endpoint. In the first stage, 18 patients were accrued and if one response was seen, the plan was to accrue additional 14 patients for total of 32 patients. Secondary endpoints were PFS, OS and safety profile. Results: Median age was 64.5 (range: 28-86) years and the primary sites of tumor were intrahepatic cholangiocarcinoma 64.7%, extrahepatic 2.9%, and gallbladder 32.4%. 17 (50.0%) of the patients were female. Twenty pts (59%) failed 1 line of therapy and 14 pts (41%) failed more than one line of therapy. Thirty-four pts received at least 1 dose of nivolumab of whom 29 pts (1 pt withdrew consent and 4 pts came off the study due to clinical progression) were evaluable for response rate. Out of 29 pts, 5 pts (17%) achieved PR and 11 pts (38%) achieved SD. DCR was 55%. Four patients who responded were all microsatellite stable and still remain on treatment (2 pts have durations of response > 12 months). For all 34 pts with median follow up of 8 months, median PFS was 3.5 months (95% CI: 2.1-7.6) and the median OS has not been reached. 6-month OS was 76.3%. Most common treatment related AEs(TRAE) were fatigue (23.5%) and elevated AST and ALT (15% and 11%). Grade III TRAEs were seen in 7pts (21%); most common were elevated bilirubin (3%) and elevated alkaline phosphatase (6%). There were no grade IV or V toxicities reported. Tissue samples were collected in all pts with planned correlative studies underway. Conclusion: The primary endpoint of ORR was met. Nivolumab was well tolerated and has shown promising efficacy in refractory BTC including durable responses lasting over 1 year. Further randomized trial is warranted in refractory BTC.
LGG-33. MEK-INHIBITOR MONOTHERAPY TO TREAT CONCURRENT OPTIC GLIOMA AND METASTATIC NEUROBLASTOMA IN A PATIENT WITH NEUROFIBROMATOSIS TYPE 1 (NF1)
Authors: Jennifer Belsky, Richard Graham, Jeffery Leonard, Jonathan Finlay, Jeremy Jones, Daniel Boué, Mark Ranalli, Mohamed AbdelBaki
Journal: Neuro-Oncology (2018)

Neurofibromatosis type 1 (NF1) is a common autosomal dominant condition caused by mutation in the NF1 tumor-suppressor gene which encodes neurofibrin, a regulator of cell proliferation through the RAS/MAPK pathway. NF1 patients frequently develop central nervous system low-grade gliomas (LGGs), but are also at increased risk for developing malignant tumors such as neuroblastoma which combined are associated with worse prognosis. The association between NF1 and neuroblastoma has been well established, though rarely reported, and its molecular basis still requires further investigation. Additionally, MEK inhibition via disruption of the RAS/MAPK pathway has been shown to be effective in neuroblastoma models in vitro, and is currently being tested in several LGG clinical trials. Co-occurrence of both tumors in a patient with NF1 is exceedingly rare and has been reported only once thus far. Here, we report on the first case in the literature for the use of a MEK inhibitor in a seven years old NF1 patient with high-risk metastatic neuroblastoma and optic pathway glioma without BRAF mutation or fusion. The patient is currently maintained on MEK inhibitor monotherapy for over a year with minimal dermatological side effects. Significant radiographic improvement in the optic pathway glioma as well as stability in the metastatic neuroblastoma has been demonstrated. Comprehensive clinical molecular testing of both tumors is currently pending.
Vascular endothelial growth factor regulation of endothelial nitric oxide synthase phosphorylation is involved in isoflurane cardiac preconditioning
Authors: Yanan Liu, Mark Paterson, Shelley L Baumgardt, Michael G Irwin, Zhengyuan Xia, Zeljko J Bosnjak, Zhi-Dong Ge
Journal: Cardiovascular Research (2018)

Abstract Aims Previous studies indicate that nitric oxide derived from endothelial nitric oxide synthase (eNOS) serves as both trigger and mediator in anaesthetic cardiac preconditioning. The mechanisms underlying regulation of eNOS by volatile anaesthetics have not been fully understood. Therefore, this study examined the role of vascular endothelial growth factor (VEGF) in isoflurane cardiac preconditioning. Methods and results Wistar rats underwent 30 min of coronary artery occlusion followed by 2 h of reperfusion. Isoflurane given prior to ischaemia/reperfusion significantly decreased myocardial infarct size from 60 ± 1% in control to 40 ± 3% (n = 8 rats/group, P &lt; 0.05). The beneficial effects of isoflurane were blocked by neutralizing antibody against VEGF (nVEGF). Coronary arterial endothelial cells (ECs) alone or together with cardiomyocytes (CMs) were subjected to hypoxia/reoxygenation injury. The expression of VEGF and eNOS was analysed by western blot, and nitric oxide was measured by ozone-based chemiluminescence. In co-cultured CMs and ECs, isoflurane administered before hypoxia/reoxygenation attenuated lactate dehydrogenase activity and increased the ratio of phosphorylated eNOS/eNOS and nitric oxide production. The protective effect of isoflurane on CMs was compromised by nVEGF and after VEGF in ECs was inhibited with hypoxia inducible factor-1α short hairpin RNA (shRNA). The negative effect of hypoxia inducible factor-1α shRNA was restored by recombinant VEGF. Conclusion Isoflurane cardiac preconditioning is associated with VEGF regulation of phosphorylation of eNOS and nitric oxide production.
T cell–intrinsic prostaglandin E2-EP2/EP4 signaling is critical in pathogenic TH17 cell–driven inflammation
Authors: Jinju Lee, Tomohiro Aoki, Dean Thumkeo, Ratklao Siriwach, Chengcan Yao, Shuh Narumiya
Journal: Journal of Allergy and Clinical Immunology (2018)

IL-23 is the key cytokine for generation of pathogenic IL-17-producing helper T (T
Glycemic Control in Nonpregnant Adults With Type 2 Diabetes
Authors: Elizabeth L. Tung, Andrew M. Davis, Neda Laiteerapong
Journal: JAMA (2018)

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Показатели цитокинов у детей с гепатобилиарной патологией в сочетании с паразитозами
Authors: T.V. Sorokman, N.A. Popelyuk, L.V. Shvygar
Journal: GASTROENTEROLOGY (2018)

Актуальность. Гепатобилиарная патология (ГБП) у детей имеет тенденцию к неуклонному росту, а сама патология характеризуется рядом особенностей, отсутствующих у взрослых. Цель: исследовать особенности цитокинового профиля у детей с гепатобилиарной патологией на фоне паразитозов. Материалы и методы. Основную клиническую группу составили 54 ребенка в возрасте от 8 до 18 лет с ГБП. Группу сравнения составили 25 практически здоровых детей, сопоставимых по возрасту и полу с основной клинической группой. Результаты. Поражение гепатобилиарного участка преобладало у детей младшего школьного возраста. У 64,8 % пациентов с ГБП были диагностированы гельминтозы или лямблиоз. Уровень интерлейкина-4 (IL-4) у детей с ГБП превышал уровень у детей группы сравнения почти в 11 раз, фактора некроза опухоли альфа (TNF-α) — в 6 раз. Самая высокая концентрация IL-4 и TNF-α зарегистрированa у пациентов с ГБП на фоне токсокароза и аскаридоза. Выводы. В структуре ГБП у детей преобладали функциональные расстройства билиарного тракта. У детей с ГБП и сопутствующими паразитозами (особенно аскаридозом и токсокарозом) уровни IL-4 и TNF-α достоверно выше показателей у детей без сопутствующего паразитоза.
RONC-07. THE TALE OF 100 DIPGs AND RADIOTHERAPY
Authors: Rahul Krishnatry, Jayant Sastri Goda, Amita Kadam, Tejpal Gupta, Girish Chinnaswamy, Rakesh Jalali, Vijay Patil, Amit Janu
Journal: Neuro-Oncology (2018)

DIPG is one of the most aggressive tumors of children leading to brain-tumor-related death. We reviewed records of all DIPG patients from Jan 2015 to date. 100 patients identified with mean age-at-diagnosis 7.9years (49% males, mean duration of symptoms:45 days), with classical radiology and satisfied minimum 2/3clinical criteria (47.5%) and 17% Lansky performance score<50. 26 patients opted best supportive care and 74 took radiotherapy(partial treatment:7-13 fractions/1.8Gy each:3, hypofractionation:1, and 51-60Gy:70). Additionally, patients received concurrent and/or adjuvant temozolomide(6), valproic acid(5), others(5). Nine patients who progressed clinic-radiologically at the mean post-RT period of 9.2(5-16)months, received re-RT(30.6-45Gy/1.8Gy per fraction; mean:41.7Gy). The median overall survival(OS) for all patients was 6 months with 6,12,24 month OS of 62.7 + 5, 36.1 + 5.5 and 8.9 + 4.1% respectively. The median survival of patients with no RT was 1 month. The patient with any radiotherapy, median OS was 8 months and OS at 6,12,24 months was 80.3 + 4.9, 40.7 + 6.8 and 11.8 + 5.3% respectively. The median OS for patients who received partial dose/hypofractionated versus full-dose radiotherapy was 3 versus 8 months respectively(p=0.0001). The patients who received single-time full dose versus reRT the median OS and OS at 6,12,24 was 7 versus15 months; and 80.7 + 5.5 versus100%; 40.3 + 7.7 versus87.5 + 11.7% and 13.2 + 6.6% versus 14.6 + 13.5% respectively(p=0.05). The reRT improved clinical symptoms in all patients ranging 20-100% with the ability to withdraw steroids in all patients post reRT and no adverse events. Radiotherapy remains the most promising therapy for DIPG. Re-RT with higher doses can have a larger impact and should be studied prospectively in a trial setting.
MBRS-17. STIMULATION OF MEDULLOBLASTOMA STEM CELLS DIFFERENTIATION BY A PEPTIDOMIMETIC TARGETING NEUROPILIN-1
Authors: Caifeng Gong, Julie Valduga, Alicia Chateau, Mylène Richard, Nadia Pellegrini-Moise, Muriel Barberi-Heyob, Pascal Chastagner, Cédric Boura
Journal: Neuro-Oncology (2018)

Medulloblastoma (MB) is the most common malignant pediatric brain tumor. Despite the progress of new treatments, the risk of recurrence, morbidity, and death remains important. The neuropilin-1 (NRP-1) receptor has recently been implicated in tumor progression of MB, which seems to play an important role in the phenotype of cancer stem cells. Targeting this receptor appears to be an interesting strategy to promote MB stem cells differentiation. Cancer stem-like cells of 3 MB cell lines (DAOY, D283-Med and Med-D341) in different molecular subgroups were obtained by in vitro enrichment. These models were characterized by an increase of NRP-1 and cancer stem cell markers (CD15, CD133 and Sox2), meanwhile a diminution of the differentiated cell marker Neurofilament-M (NF-M) was observed. Our previous work investigated several potential innovative peptidomimetics that specifically targeted NRP-1 and showed that MR438 had a good affinity for NRP-1. This small molecule decreased the self-renewal capacity of MB stem cells for the 3 cell lines and reduced the invasive ability of DAOY and D283 stem cells while NRP-1 expression and cancer stem cell markers decreased at the same time. Possible molecular mechanisms were explored and showed that phosphorylation of AKT and ERK proteins in PI3K/AKT and MAPK pathways significantly decreased for DAOY-MS cells after treatment. Finally, our results highlighted that targeting NRP-1 with MR438 is a potential new strategy to differentiate MB stem cells and improve chance to cure.
Cell-Specific Functions of ADAM17 Regulate the Progression of Thoracic Aortic Aneurysm
Authors: Mengcheng Shen, Mei Hu, Paul W.M. Fedak, Gavin Y. Oudit, Zamaneh Kassiri
Journal: Circulation Research (2018)

ADAM17 (a disintegrin and metalloproteinase-17) is a membrane-bound enzyme that regulates bioavailability of multiple transmembrane proteins by proteolytic processing. ADAM17 has been linked to several pathologies, but its role in thoracic aortic aneurysm (TAA) has not been determined.The objective of this study was to explore the cell-specific functions of vascular ADAM17 in the pathogenesis and progression of TAA.In aneurysmal thoracic aorta from patients, ADAM17 was increased in tunica media and intima. To determine the function of ADAM17 in the major cells types within these regions, we generated mice lacking ADAM17 in smooth muscle cells (SMC; Adam17f/f/Sm22Cre/+ ) or endothelial cells (Adam17f/f/Tie2Cre/+ ). ADAM17 deficiency in either cell type was sufficient to suppress TAA dilation markedly and adverse remodeling in males and females (in vivo) although through different mechanisms. ADAM17 deficiency in SMCs prevented the contractile-to-synthetic phenotypic switching in these cells after TAA induction, preventing perivascular fibrosis, inflammation, and adverse aortic remodeling. Loss of ADAM17 in endothelial cells protected the integrity of the intimal barrier by preserving the adherens junction (vascular endothelial-cadherin) and tight junctions (junctional adhesion molecule-A and claudin). In vitro studies on primary mouse thoracic SMCs and human primary aortic SMCs and endothelial cells (±ADAM17 small interfering RNA) confirmed the cell-specific functions of ADAM17 and demonstrated the cross-species validity of these findings. To determine the impact of ADAM17 inhibition in treating TAA, we used an ADAM17-selective inhibitor (PF-548) before or 3 days after TAA induction. In both cases, ADAM17 inhibition prevented progression of aneurysmal growth.We have identified distinct cell-specific functions of ADAM17 in TAA progression, promoting pathological remodeling of SMC and impairing integrity of the intimal endothelial cell barrier. The dual impact of ADAM17 deficiency (or inhibition) in protecting 2 major cell types in the aortic wall highlights the unique position of this proteinase as a critical treatment target for TAA.
DEV-19. THE ROLE OF COMBAT (COMBINED ORAL METRONOMIC BIODIFFERENTIATING ANTIANGIOGENIC TREATMENT) IN HIGH-RISK AND RELAPSED MEDULLOBLASTOMA: A SINGLE INSTITUTION EXPERIENCE
Authors: Girish Chinnaswamy, Hari Sankaran, Vasudev Bhat, Anand KC, Megha Saroha, Maya Prasad, Tushar Vora, Ayushi Sahay, Rahul Krishnatry, Sona Pungavkar, Amit Janu, Tejpal Gupta, Rakesh Jalali, Shripad Banavali
Journal: Neuro-Oncology (2018)

We retrospectively reviewed the efficacy and feasibility of COMBAT metronomic chemotherapy in high risk and relapsed medulloblastoma from April 2011 to December 2016. Post-surgery high risk medulloblastoma or relapsed medulloblastoma who were started on COMBAT regimen after completion of conventional therapy were included in this analysis. COMBAT regimen consists of low dose temozolomide, etoposide, sodium valproate and 13-cisretinoic acid administered in 12-weekly cycles. 39 children (median age, 9 years; median follow-up, 27.7 months; male:female ratio, 5.5:1) were started on COMBAT during the study period, of which 19 (48.7%) were started after completion of conventional therapy and 20 (51.3%) were started at relapse. Molecular data was available for 17 children (WNT – n=2; SHH, n=3; Group 3, n=5; Group 4, n =7). 2-year progression free survival (PFS) after starting COMBAT was 83.9% (95%CI: 49.4–95.7) and 25.8% (95% CI: 6.5–51.1%) for upfront therapy and relapsed medulloblastoma at presentation respectively. 2-year overall survival was 92.3% (95% CI: 56.6–98.9%) and 67.4% (95% CI: 41.0–84.0%) for upfront therapy and relapsed medulloblastoma at presentation respectively. Only 1 child developed secondary AML and warranted discontinuation of COMBAT therapy. COMBAT regimen is a well-tolerated and effective treatment option after completion of conventional treatment for children with high risk medulloblastoma. Future ongoing studies will further delineate the role of COMBAT in high risk medulloblastoma based on molecular subtypes.
LGG-23. REPEATED PROGRESSIONS IN PEDIATRIC CHIASMATIC-HYPOTHALAMIC GLIOMAS (CHG): CAN WE IDENTIFY SUCCESSFUL TREATMENT STRATEGIES?
Authors: Daniela Kandels, René Schmidt, Monika Warmuth-Metz, Brigitte Bison, Rolf-Dieter Kortmann, Beate Timmermann, Torsten Pietsch, Astrid K Gnekow
Journal: Neuro-Oncology (2018)

Recommendations for primary treatment of pediatric CHG are well established, but comprehensive therapeutic strategies for subsequent progressive disease are needed. We evaluated salvage therapies applied within the German/Swiss SIOP-LGG-2004/LGG-register cohort. 446 patients with CHG among 2589 patients with low-grade glioma were registered between 2004 and 2015. Neurofibromatosis type 1: 209; histology: 159 pilocytic astrocytomas, 18 pilomyxoid astrocytomas, 27 other histologies and 242 radiological diagnosis. Resection (complete/subtotal/partial) was achieved in 115, biopsy in 89 patients. Only 131/446 patients remained observed without treatment for up to12.8 years. First non-surgical treatment was chemotherapy (ChT) for 268 (263 vincristine/carboplatin ±etoposide) and radiotherapy (RT) for 47. After primary treatment 136/315 patients progressed (median time 2.2 years), of whom 107 received second- (85ChT, 22RT), 54 third- (39ChT, 15RT), 15 fourth- (11ChT, 4RT) and 5 fifth-line therapy (2ChT, 3RT). Five-year overall survival (OS) of the complete cohort is 96.8%. Although 23/53 infants (age <1year) and 21/44 patients with dissemination needed 3-5 therapies, 5-year-OS for infants is still 83.7% and 84.9% for dissemination, respectively. While successive treatments mirrored the distribution of general options, the percentage of patients receiving RT increased up to 30-60% for fourth and fifth therapy. Multiple chemotherapies do not seem to hamper the effect of subsequent radiotherapy. Following vincristine/carboplatin ±etoposide second-line platinum-based ChT achieved 53.4% 2-year progression-free survival vs. 30.3% with vinblastine. Progression/relapse of pediatric CHG following first-line standard treatment still allows disease control for most patients with multiple treatment lines. Future studies should focus upon the effect on vision and integrate targeted treatment.