tbuckley/cabot-search huggingface dataset:
P10.18 The impact of clinical functional MRI on surgical decision making in low grade glioma - a survey of Canadian neurosurgeons
Authors: S. E. Kosteniuk, J. C. Lau, J. F. Megyesi
Journal: Neuro-Oncology (2017)

BACKGROUND: The goal of brain tumour resection is maximal removal of unhealthy tissue with minimal disruption of neurological function. For tumours in eloquent cortical regions, the balance between maximal tumour resection and preservation of functional tissue is exceedingly delicate. The tools available to surgeons to determine patients’ functional anatomy tend to be invasive. Functional magnetic resonance imaging (fMRI) is a non-invasive, and increasingly popular tool for functional mapping in neurosurgical patients. However, no widely used guidelines for the use of fMRI in neurosurgical patients currently exist. In this study, we are conducting a survey of Canadian neurosurgeons to elucidate how they use fMRI, and how it impacts their approach to patients with intracranial low grade glioma (LGG). METHODS: A 15-25 minute survey was created using an online survey tool. It has been distributed to neurosurgery staff and trainees at the London Health Sciences Centre (LHSC) through email, and in the future will be distributed to members of the Canadian Neurosurgical Society (CNS). The survey consists of two sections - background, and case-based decision making. In the background section, respondents are asked questions related to their practice, typical approach to LGG, and use of fMRI. In the case-based section, five cases of patients with LGG who underwent preoperative fMRI are presented. Initially structural MRI and clinical details of each case are provided, and respondents are asked about their preferred management, confidence in their preferred treatment, and predicted risk of surgical complications. Subsequently, respondents are also presented with fMRI details of each case, and asked an identical series of questions. Results: We collected 6 surveys of 24 distributed to neurosurgery staff and trainees at LHSC. On average, respondents stated they order preoperative fMRI for 9% of brain tumour patients. 67% of respondents stated they are comfortable ordering and interpreting fMRI for brain tumour patients, 17% stated they are not comfortable, and 17% stated they are neither comfortable nor uncomfortable. No respondents expressed a preference for early surgical intervention for LGG patients, 50% prefer watchful waiting, and 50% expressed no preference. In the case-based section, fMRI data did not tend to affect respondents’ preferred treatment, confidence in their treatment, or their predicted risk of surgical complications. We expect to collect 59-147 completed national surveys, based on a predicted 20-50% response rate of 293 CNS members. Conclusions: We expect this study to elucidate how Canadian neurosurgeons use fMRI in practice, and if fMRI allows them to recommend more aggressive surgical treatment for LGG patients with greater confidence.
OS06.3 Characterisation of human brain tumour initiating cells leading invasion
Authors: V. J. Leidgens, M. Alieva, X. Lu, N. Patwary, E. Kerkhoff, M. J. M. Proescholdt, A. Vollmann-Zwerenz, J. van Rheenen, C. A. Klein, P. Hau
Journal: Neuro-Oncology (2017)

Introduction: Glioblastoma (GBM) belongs to the most aggressive cancers. Main pathophysiological feature of GBM is fast and widespread invasion of the brain parenchyma by a subpopulation of progenitor tumour cells, rendering localized therapies ineffective. In addition, brain tumour initiating cells (BTIC) from GBM may repopulate the tumour site after initially effective treatments. Thus, the invasive progenitor tumour cell fraction is a strategic prime target for early and sustained anti-invasion therapies. To date, the dependency on and interaction with the microenvironment of progenitor cells and their adaptive development from the tumour cell fraction has not been thoroughly investigated. Methods: With organotypic brain slice cultures (OBSC), single cell RNA expression analysis and bioinformatics workup, we established a novel integrated approach to investigate the expression profile of invasion leading cells. A micromanipulator adapter was developed to isolate different three subpopulations within human GBM progenitor cells: leader, follower, and stationary, from the OBSCs. In comparison, we use long-term intravital imaging to analyse the behaviour and interaction of the three cellular fractions with each other and the microenvironment in vivo. Imaging through a cranial window in the brain of a living mouse enables us to visualize single tumour cells. Using a photoswitchable vector expressed in BTICs we specifically label and isolate leader, follower, and stationary cells separately to compare leader cell behaviour in vivo, in situ, and in the patient situation. Findings: The in situ OBSC model is a valuable tool to analyse migration and invasion in conditions simulating normal brain tissue including some microenvironmental influences. This allowed us to monitor human BTIC cell invasion in real time. Invasive cells emerge from the initial cell population, driving invasion into the surrounding tissue. Those leader cells differ in morphology and behaviour from stationary cells, which remain at the implantation site. A subsequent microarray analysis of single cells revealed that leader cells have a markedly distinct expression pattern in comparison to follower and stationary cells. This leader cell-specific expression signature is currently verified in fresh patient tumour biopsies, other BTICs analysed in the OBSC as model, and in the cranial window model. Updated results will be presented at the WFNOS meeting. Outlook: We showed that invasive leader cells have a specific functional and molecular profile. A thorough characterization of these cells in respect to their interaction with and response to the microenvironment that may be involved in the process of transforming cells into invasive leader cells is ongoing. We hypothesize that a deep characterization of these events will shed light on the chronology of one of the gliomagenesis milestones, namely invasion.
A Highly Selective Anti-ROR1 Monoclonal Antibody Inhibits Human Acute Myeloid Leukemia CD34+ Cell Survival and Self-Renewal.
Authors: Larissa Balaian, Anil Sadarangani, George F. Widhopf, Rui-kun Zhong, Charles Prussak, Marco A. Marra, John E Dick, Mark D. Minden, Edward D. Ball, Dennis A. Carson, Catriona Jamieson, Thomas J. Kipps
Journal: Blood (2012)
Complement factor P is a ligand for the natural killer cell–activating receptor NKp46
Authors: Emilie Narni-Mancinelli, Laurent Gauthier, Myriam Baratin, Sophie Guia, Aurore Fenis, Ala-Eddine Deghmane, Benjamin Rossi, Patrick Fourquet, Bertrand Escalière, Yann M. Kerdiles, Sophie Ugolini, Muhamed-Kheir Taha, Eric Vivier
Journal: Science Immunology (2017)

Innate lymphoid cells (ILCs) are involved in immune responses to microbes and various stressed cells, such as tumor cells. They include group 1 [such as natural killer (NK) cells and ILC1], group 2, and group 3 ILCs. Besides their capacity to respond to cytokines, ILCs detect their targets through a series of cell surface-activating receptors recognizing microbial and nonmicrobial ligands. The nature of some of these ligands remains unclear, limiting our understanding of ILC biology. We focused on NKp46, which is highly conserved in mammals and expressed by all mature NK cells and subsets of ILC1 and ILC3. We show here that NKp46 binds to a soluble plasma glycoprotein, the complement factor P (CFP; properdin), the only known positive regulator of the alternative complement pathway. Consistent with the selective predisposition of patients lacking CFP to lethal Neisseria meningitidis (Nm) infections, NKp46 and group 1 ILCs bearing this receptor were found to be required for mice to survive Nm infection. Moreover, the beneficial effects of CFP treatment for Nm infection were dependent on NKp46 and group 1 NKp46+ ILCs. Thus, group 1 NKp46+ ILCs interact with the complement pathway, via NKp46, revealing a cross-talk between two partners of innate immunity in the response to an invasive bacterial infection.
Final results from a phase II trial of systemic chemotherapy in a small cell urothelial cancer: Evidence supporting neoadjuvant chemotherapy from the M.D. Anderson Cancer Center
Authors: A. O. Siefker-Radtke, A. M. Kamat, H. Grossman, D. L. Williams, C. P. Dinney, R. E. Millikan
Journal: Journal of Clinical Oncology (2007)

5083 Background: Previously reported retrospective data supported a potential role for neoadjuvant chemotherapy in small cell urothelial cancer (SCUC). We now report final results from a phase II clinical trial in SCUC. Methods: Since 2001, 30 patients with biopsy proven SCUC received alternating doublet chemotherapy with Ifosfamide + Doxorubicin, and Etoposide + Cisplatin. Patients with surgically resectable disease (&lt;=cT4aN0M0) received a total of 4 cycles followed by cystectomy, while those with unresectable disease (&gt;=cT4b, N+, or M+) received 2 cycles beyond maximal response. Results: Neoadjuvant chemotherapy was given in 18 patients (cT2:14, cT3:4), while 12 patients were treated for metastatic SCUC. For those receiving neoadjuvant therapy, the median OS is 58 months, with a 5-year survival of 48%; 8 remain alive and NED beyond 2.5 years. There have been only 5 deaths for the neoadjuvant group (3 SCUC, 1 post-op infection, 1 AML). For those with metastatic disease, the median OS is 14 months. Two were rendered resectable with chemotherapy (cT4b:1,N+:1); 1 died of recurrent SCUC, while the other is currently undergoing therapy for TCC of the ureter. Brain metastases developed in 7 patients (cT3b:2, initial M+:5). Chemotherapy has been well-tolerated with only 2 G4 toxicities (catheter infection and neutropenia). The most frequent G3 toxicities include transfusion (10), neutropenic fever (7), infection (5), and vomiting (3). There was only one post-surgical death; a case of sepsis in a patient with diverticulitis and abscess requiring sigmoid colon resection. Conclusions: These prospective results, which are consistent with our previously reported retrospective review, provide additional support for 4 cycles of neoadjuvant chemotherapy in the setting of SCUC. Unfortunately, once metastases are present, the prognosis remains poor with few long-term survivors. These results may also predict a patient subset for which prophylactic cranial irradiation may be potentially beneficial. No significant financial relationships to disclose.
Ability of individual patient health parameters to predict malnutrition among elderly stem cell transplant patients.
Authors: Nizar Bhulani, Holly Michelle Holmes, Robert Morgan
Journal: Journal of Clinical Oncology (2017)

e21521 Background: Increasing number of geriatric patients are now being considered as suitable candidates for allogeneic hematopoietic cell transplantation (HCT). Malnutrition being a common comorbidity in older cancer patients with no gold standard in malnutrition screening tools, it warrants for a better understanding of the health of geriatric cancer patients from a nutrition stand point. This study was pursued to evaluate individual patient parameters to predict malnutrition among elderly stem cell transplant patients. Methods: A retrospective cohort analysis was conducted on patients eligible for allogeneic HCT at the MD Anderson Cancer Center. Nutrition was assessed using the Mini Nutritional Assessment tool. Individual parameters to predict malnutrition included body mass index of less than 24 and weight loss of more than 3 kgs in the past 3 months. Statistical analysis was conducted using SPSS, version 23. Results: Mean age of the study participants was 65 years. Majority of the study population had the diagnosis of acute myelogenous leukemia (AML) at the time evaluation. The mean BMI of the study participants was 28.91 +- 4.77 while the mean MNA score was 24.95 +- 3.39. There was no association found between patient characteristics and history of weight loss or abnormal BMI. There was a significant association (p &lt; 0.001) found between loss of more than 3 kg weight and an abnormal MNA score. There was no association found between any of the patient characteristics and abnormal BMI with abnormal MNA. The sensitivity of weight loss in comparison with MNA score was 62.5% and the specificity was 91%, thus, having a positive and negative predictive value of 77% and 84% respectively. Given that 86% of our patients were either overweight or obese at the time of evaluation, from those who were under weight, 100% had an abnormal MNA and 50% of normal weight patients had an abnormal MNA. Conclusions: The significant association between weight loss and poor MNA status shows that we are moving in the right direction to provide answers to nutrition status using individual patient health parameters.
P01.11 New targets for glioblastoma revealed by chemical biology fingerprinting
Authors: D. Finlay, H. Dhruv, C. Hauser, J. Kiefer, S. Kim, T. Long, S. Peng, G. Speyer, M. Berens, K. Vuori
Journal: Neuro-Oncology (2017)

Introduction: Glioblastoma multiforme (GBM) is a particularly aggressive brain cancer with extremely inadequate treatment options. Even with resection, ionizing radiation and use of the alkylating agent temozolomide the median survival is only 14.3 months. Therefore, there is a great need for novel therapeutic intervention points. MATERIAL AND METHODS: We have developed methodologies and protocols for the isolation and culture of patient derived GBM cells that preserve the stem-like cell population believed to be involved in treatment resistance and reappearance. Importantly the cells are never cultured in the presence of fetal bovine serum in order to prevent aberrant selection of sub-clones that no longer match the original disease. Results: Using RNA sequencing profiling we show that the samples are similar to the original cancers and that we have multiple patient derived cultures that fall into subgroups reflected by traditional GBM sub-stratifications. In a technique we call chemical biology fingerprinting (CBF) we use dedicated, yet cancer-pertinent, drug libraries to profile multiple GBM samples for subtype specific vulnerabilities. Furthermore all our CBF screening is carried out using 3D neurosphere cultures that better recapitulate the nutrients and oxygen gradients of cancers in vivo. Drug penetration and correct cellular architecture are also better assessed in these systems than in traditional monolayer cell culture and our models are amenable to heterotypic cultures with relevant microenvironmental and stromal factors. Conclusions: In summary, we show generation of patient derived samples suitable for relevant drug screening and use chemical biology fingerprinting to discover novel targets in the disease. Supported by NIH U01CA168397.
CTEN and LKB1: Novel tumor biomarkers that give insight into resistance and response to tyrosine kinase inhibitor (TKI)-based therapies.
Authors: Sarah Bacus, Scott Shell, Yosef Yarden
Journal: Clinical Cancer Research (2007)

B1  Background: The hyper-expression and activation of the erbB family of receptor tyrosine kinases plays a significant role in the development of many cancer types. The complexities and heterogeneity of tumor types necessitates the ongoing search for additional biomarkers to better classify a particular patient’s tumor profile for successful individualized treatment. Here we show that the reciprocal change in expression of Tensin3 and CTEN, proteins involved in Actin fiber binding, induces increased motility in EGFR- and HER-2-driven tumors and that down-regulation of CTEN was observed upon TKI treatment. Furthermore, we show that the presence of LKB1, a master regulator of cellular metabolism and activator of AMP-activated protein kinase (AMPK), is necessary for effective TKI-therapy.  Methods: Western blot and IHC: EGFR, pEGFR, HER-2, pHER-2, pNFkB, pAMPK, pACC, peEF2, p53, LKB1, and Actin (Cell Signaling); and CTEN (Y. Yarden). Cells: AU565 IBC and A549 lung carcinoma cell lines were grown in RPMI 1640 media supplemented in 10% FBS. Treatments: EGF and GW2974 (Sigma); TNF-alpha (R&D Systems), Herceptin (Genentech).  Results: Our results show that EGF treatment down-regulates Tensin 3 and up-regulates CTEN in EGFR- and HER-2-driven tumor cell lines and tumors resulting in increased cellular motility. Furthermore, while the expression of CTEN correlates with high EGFR and HER-2 expression in breast cancer, treatment of breast cancer patients with a dual EGFR/HER-2 inhibitor resulted in a significant down-regulation of CTEN. In addition, the intact LKB1/pAMPK/pACC pathway correlated with TKI response while LKB1-deficient cells lines that are unable to activate the AMPK pathway are non-responsive to TKI therapies. This was shown by the inability of AMPK to activate the downstream effector proteins pACC and peEF2 in the context of LKB1 mutation/deletion. Furthermore, even in the presence of an intact LKB1-AMPK pathway, response is further contingent on wild type p53. IHC staining of a responding EGFR-positive, HER-2 over-expressing, ER-negative breast cancer patients to TKI therapy demonstrates that the presence of LKB1, pACC, CTEN, and wild-type p53 are strong biomarkers to predict a positive response to TKI-based therapy.  Conclusion: Our findings support the incorporation of CTEN, LKB1, pAMPK, pACC and p53 as additional biomarkers to aid in the targeted therapy choices for cancer patients. By combining these biomarkers to the well-documented list of traditional erbB-related biomarkers, EGFR- and HER-2-driven cancer patients can benefit from the most efficacious personalized treatment possible.
P01.19 Activation of the mTOR signaling pathway in peritumoral tissues can cause glioma-associated seizures
Authors: Q. Mao, Y. Yuan
Journal: Neuro-Oncology (2017)

Epileptic seizures, the most common symptom accompanying glioma, are closely associated with tumor growth and patient quality of life. However, the association between glioma and glioma-related epilepsy is poorly understood. In fact, findings related to the location of epileptogenicity have been inconsistent in previous studies. We investigated seizure foci in patients with glioma and the corresponding association between glioma-related epilepsy and the tumoral and peritumoral microenvironment. Clinical characteristics, extracellular electrophysiology, immunohistochemistry, and western blots were conducted on 12 patients with glioma; nine patients had histories of preoperative seizures while three did not. Samples from included patients were used to identify seizure foci and mTOR pathway status. Electrophysiological recordings were conducted on 36 samples (tumor, peritumoral, and normal brain tissues) from 12 patients. Interictal-like discharges (ILDs) were observed in seven of nine peritumoral tissues obtained from patients with glioma that had experienced perioperative seizures. No ILDs were observed in any other sample groups. Western blots and immunohistochemistry for mTOR pathway proteins (mTOR and S6k) suggested that the mTOR pathway was activated in peritumoral tissues of patients with seizure history, but inactivated in patients without seizure history. Our results suggest that mTOR pathway expression in peritumoral tissues is associated with tumor-related seizures, thus providing a potential target for therapeutics aimed at simultaneously controlling gliomas and seizures.
Time from Diagnosis to Initiation of Curative Chemotherapy Affects Outcomes in DLBCL - Data from a Large Asian Cohort
Authors: Colin Phipps, Yuh Shan Lee, Chandramouli Nagarajan, Yunxin Chen, Allan ZK Goh, Lay Poh Khoo, Kevin Tay, Miriam Tao, Richard Quek, Tiffany Tang, Mohamad Farid, Soon Thye Lim, Sathish Kumar Gopalakrishnan, Nicholas F Grigoropoulos, Yvonne Loh, Daryl Tan, William YK Hwang, Yeow Tee Goh
Journal: Blood (2016)
Endoscopic full-thickness resection of fistula tract with suture closure
Authors: Austin Chiang, Andrew Storm, Hiroyuki Aihara, Christopher Thompson
Journal: Endoscopy (2017)

A 59-year-old man, with a history of Roux-en-Y gastric bypass 9 years previously, presented with chronic epigastric pain thought to be due to recurrent marginal ulceration. On diagnostic endoscopy he was found to have a 3-cm gastric pouch and a 18-mm gastrojejunal anastomotic diameter. Additionally, a 1-cm cratered ulceration on the jejunal aspect of the post-bypass anastomosis and a 3-mm fistulous opening in the distal gastric pouch were noted. The presence of bubbles when the area was flooded with water suggested a fistulous communication between the gastric pouch and the remnant stomach.
Effects of combined tiotropium/olodaterol on inspiratory capacity and exercise endurance in COPD
Authors: Denis E. O'Donnell, Richard Casaburi, Peter Frith, Anne Kirsten, Dorothy De Sousa, Alan Hamilton, Wenqiong Xue, François Maltais
Journal: European Respiratory Journal (2017)

Two replicate, double-blind, 6-week, incomplete-crossover studies (MORACTO 1 and 2) assessed the effects of tiotropium/olodaterol on inspiratory capacity and exercise endurance time in patients with moderate to severe chronic obstructive pulmonary disease. For each patient, four of five treatments were administered once daily for 6 weeks, with a 21-day washout between treatments: tiotropium/olodaterol 2.5/5 µg or 5/5 µg, tiotropium 5 µg, olodaterol 5 µg or placebo, all via the Respimat inhaler. Primary outcomes were inspiratory capacity prior to exercise and exercise endurance time during constant work-rate cycle ergometry to symptom limitation at 75% of peak incremental work rate after 6 weeks (2 h post-dose). 295 and 291 patients were treated in MORACTO 1 and 2, respectively. Tiotropium/olodaterol 2.5/5 and 5/5 µg provided significant improvements in inspiratory capacity versus placebo and monotherapies (p&lt;0.0001), and significant improvements in exercise endurance time versus placebo (p&lt;0.0001). Intensity of breathing discomfort was reduced following both doses of tiotropium/olodaterol versus placebo (p&lt;0.0001). Once-daily tiotropium/olodaterol yielded improvements in lung hyperinflation versus placebo and statistically significant improvements versus monotherapies. Tiotropium/olodaterol also showed improvements in dyspnoea and exercise tolerance versus placebo but not consistently versus monotherapies.