tbuckley/cabot-search huggingface dataset:
TMOD-09. EGFRvIII INCREASES MISMATCH REPAIR PROTEIN EXPRESSION AND IS THEREFORE A PREDICTIVE MARKER FOR TEMOZOLOMIDE RESPONSE IN O6-METHYLGUANINE-DNA METHYLTRANSFERASE NEGATIVE GLIOBLASTOMA CELLS AND TUMORS
Authors: Nina Struve, Tim Brend, Lucy Stead, Leonie Ott, Cordula Petersen, Kai Rothkamm, Susan C. Short, Malte Kriegs
Journal: Neuro-Oncology (2016)

Glioblastoma multiforme (GBM) is the most common malignant brain tumor in adults with an extremely poor prognosis. The standard therapy involves surgery followed by irradiation and temozolomide (TMZ) treatment. Epigenetic silencing of the O6-methylguanine-DNA-methyltransferase (MGMT) gene is the only predictive biomarker that is associated with TMZ response. Hence the establishment of new markers, which predict treatment response is therefore of significant interest. Approximately 20-30% of GBMs display expression of the epidermal growth factor receptor (EGFR) variant III (EGFRvIII), which is constitutively activated. The aim of the present study was to analyse the impact of endogenous EGFRvIII expression on TMZ sensitivity of cell cultures and tumor xenografts. Using isogenic pairs of MGMT methylated GBM cells we observed that EGFRvIII expression was associated with a significant increase in TMZ sensitivity in vitro and in vivo. Knockdown of EGFRvIII restored TMZ resistance, confirming EGFRvIII dependent TMZ sensitivity. TMZ sensitivity in MGMT negative cells is predominantly determined by functional mismatch repair (MMR). In agreement with this, we found that EGFRvIII expression was associated with an upregulated MMR protein expression in cells and in tumor xenografts. Remarkably even a slight decrease in MSH6 and MLH1 expression restored TMZ resistance. Moreover EGFRvIII expressing cells showed more DNA damage after TMZ treatment. In accordance with our findings statistical analysis using The Cancer Genome Atlas and published data revealed that EGFRvIII expression is associated with a significant better outcome in patients who were treated with irradiation and TMZ. In summary, we have shown that EGFRvIII expressing GBM cells, which do not express MGMT are significantly more sensitive to TMZ than their isogenic EGFRvIII negative counterparts. Our data highlight a new mechanism, which mediates TMZ sensitivity and therefore argue that EGFRvIII could be a predictive biomarker for therapeutic response to TMZ treatment in MGMT methylated GBM patients.
Prognostic Molecular and Imaging Biomarkers in Primary Glioblastoma
Authors: Edit Bosnyák, Sharon K. Michelhaugh, Neil V. Klinger, David O. Kamson, Geoffrey R. Barger, Sandeep Mittal, Csaba Juhász
Journal: Clinical Nuclear Medicine (2017)

Several molecular glioma markers (including isocitrate dehydrogenase 1 [IDH1] mutation, amplification of the epidermal growth factor receptor [EGFR], and methylation of the O6-methylguanine-DNA methyltransferase [MGMT] promoter) have been associated with glioblastoma survival. In this study, we examined the association between tumoral amino acid uptake, molecular markers, and overall survival in patients with IDH1 wild-type (primary) glioblastoma.Twenty-one patients with newly diagnosed IDH1 wild-type glioblastomas underwent presurgical MRI and PET scanning with alpha[C-11]-L-methyl-tryptophan (AMT). MRI characteristics (T2- and T1-contrast volume), tumoral tryptophan uptake, PET-based metabolic tumor volume, and kinetic variables were correlated with prognostic molecular markers (EGFR and MGMT) and overall survival.EGFR amplification was associated with lower T1-contrast volume (P = 0.04) as well as lower T1-contrast/T2 volume (P = 0.04) and T1-contrast/PET volume ratios (P = 0.02). Tumors with MGMT promoter methylation showed lower metabolic volume (P = 0.045) and lower tumor/cortex AMT unidirectional uptake ratios than those with unmethylated MGMT promoter (P = 0.009). While neither EGFR amplification nor MGMT promoter methylation was significantly associated with survival, high AMT tumor/cortex uptake ratios on PET were strongly prognostic for longer survival (hazards ratio, 30; P = 0.002). Estimated mean overall survival was 26 months in patients with high versus 8 months in those with low tumoral AMT uptake ratios.The results demonstrate specific MRI and amino acid PET imaging characteristics associated with EGFR amplification and MGMT promoter methylation in patients with primary glioblastoma. High tryptophan uptake on PET may identify a subgroup with prolonged survival.
Advanced acinic cell carcinoma harbors kinase rearrangements including BRAF kinase domain duplications
Authors: S.M. Ali, K. Fedorchak, A.B. Schrock, J. Johnson, K. Gowen, J.A. Elvin, J.-A. Vergilio, S.J. Klempner, R. Mehra, A. Ho, D. Pavlick, J. Suh, R. Bordoni, D.H. Jung, P. Stephens, C.H. Chung, J.S. Ross, V. Miller
Journal: Annals of Oncology (2016)
Carboplatin (Cb) plus nab-paclitaxel (PTX) versus docetaxel (D) for elderly squamous (Sq) non-small cell lung cancer (NSCLC) (CAPITAL study)
Authors: Y. Kogure, H. Saka, Y. Takiguchi, S. Atagi, T. Kurata, N. Ebi, A. Inoue, K. Kubota, M. Takenoyama, T. Seto, A. Kada, T. Yamanaka, M. Ando, N. Yamamoto, A. Gemma, Y. Ichinose
Journal: Annals of Oncology (2016)
Identification of exosomes in non-Hodgkin B-cell lymphomas. Prognostic usefulness in patients treated with rituximab-chemotherapy: a prospective, multicenter correlation study by the Spanish Lymphoma Oncology Group (GOTEL)
Authors: M. Provencio, M. Rodriguez-Balada, B. Cantos, C. Quero, R. García Arroyo, A. Rueda, C. Maximiano, D. Rodriguez Abreu, A. Sanchez, V. Garcia
Journal: Annals of Oncology (2016)
CD45 Defines Signaling Thresholds Critical for Proliferation and Apoptosis in Myeloma Cells.
Authors: Shangqin Liu, Hideaki Ishikawa, Naohiro Tsuyama, Saeid Abroun, Fu-Jun Li, Ken-ichiro Otsuyama, Xu Zheng, Zi Ma, Yasuko Maki, Masanori Obata, Michio M. Kawano
Journal: Blood (2004)
An 111In-Pentetreotide Positive Sclerosing Pneumocytoma
Authors: Giordano Savelli, Claudio Bnà, Claudia Zambelli, Sonia Illuminati, Luke Bonello
Journal: Clinical Nuclear Medicine (2017)

A 43-year-old woman had an incidental lung mass identified on shoulder x-ray performed for pain. Contrast-enhanced CT showed a 38-mm mass in the medial segment of the right middle lobe, with features suggestive of carcinoid tumor. A 111In-pentetreotide scan showed intense uptake; furthermore, fine needle aspiration biopsy yielded neuroendocrine cells confirming the carcinoid hypothesis. However, definitive surgical histology showed a sclerosing pneumocytoma. This could potentially suggest that such rare tumors, with metastatic potential, could respond to somatostatin analogue treatment.
Chemo-Resistance in Diffuse Large Cell Lymphoma: Novel Drug Combinations Targeting NFAT/NF-Kb Growth/Survival/Chemo-Resistance Signaling Pathways in Validated Novel Experimental Systems
Authors: Lan V Pham, Archito T. Tamayo, Changping Li, John Lee, Luis Fayad, Richard J. Ford
Journal: Blood (2011)
Evaluation of quality of life in early breast cancer disease free survivors. a cross sectional survey
Authors: D. Aiello, S. Patti, M. Alì, M.V. Sanò, S. Virgilio, E. Taibi, V.M.G. Di Leo, G. Fallica, M. Caruso, R.A. Aiello
Journal: Annals of Oncology (2016)
Egress of sperm autoantigen from seminiferous tubules maintains systemic tolerance
Authors: Kenneth S.K. Tung, Jessica Harakal, Hui Qiao, Claudia Rival, Jonathan C.H. Li, Alberta G.A. Paul, Karen Wheeler, Patcharin Pramoonjago, Constance M. Grafer, Wei Sun, Robert D. Sampson, Elissa W.P. Wong, Prabhakara P. Reddi, Umesh S. Deshmukh, Daniel M. Hardy, Huanghui Tang, C. Yan Cheng, Erwin Goldberg
Journal: Journal of Clinical Investigation (2017)

Autoimmune responses to meiotic germ cell antigens (MGCA) that are expressed on sperm and testis occur in human infertility and after vasectomy. Many MGCA are also expressed as cancer/testis antigens (CTA) in human cancers, but the tolerance status of MGCA has not been investigated. MGCA are considered to be uniformly immunogenic and nontolerogenic, and the prevailing view posits that MGCA are sequestered behind the Sertoli cell barrier in seminiferous tubules. Here, we have shown that only some murine MGCA are sequestered. Nonsequestered MCGA (NS-MGCA) egressed from normal tubules, as evidenced by their ability to interact with systemically injected antibodies and form localized immune complexes outside the Sertoli cell barrier. NS-MGCA derived from cell fragments that were discarded by spermatids during spermiation. They egressed as cargo in residual bodies and maintained Treg-dependent physiological tolerance. In contrast, sequestered MGCA (S-MGCA) were undetectable in residual bodies and were nontolerogenic. Unlike postvasectomy autoantibodies, which have been shown to mainly target S-MGCA, autoantibodies produced by normal mice with transient Treg depletion that developed autoimmune orchitis exclusively targeted NS-MGCA. We conclude that spermiation, a physiological checkpoint in spermatogenesis, determines the egress and tolerogenicity of MGCA. Our findings will affect target antigen selection in testis and sperm autoimmunity and the immune responses to CTA in male cancer patients.
Meta-analysis of chemotherapy in head and neck cancer (MACH-NC): An update on 100 randomized trials and 19,248 patients, on behalf of MACH-NC group
Authors: P. Blanchard, C. Landais, C. Petit, Q. Zhang, V. Grégoire, J. Tobias, B. Burtness, M.G. Ghi, F. Janot, J. Overgaard, G. Wolf, F. Lewin, R. Hitt, R. Corvo, V. Budach, A. Trotti, C. Fortpied, A. Hackshaw, J. Bourhis, J.-P. Pignon
Journal: Annals of Oncology (2016)
TMIC-03. IMAGING BRAIN TUMOR-ASSOCIATED NEUROINFLAMMATION IN ANIMAL MODELS USING FERUMOXYTOL
Authors: Leslie Muldoon, Daniel Schwartz
Journal: Neuro-Oncology (2016)

In the brain tumor microenvironment, non-neoplastic cells with inflammatory function such as tumor-associated macrophages can influence the survival, proliferation and infiltrative activity of cancer cells. The ultrasmall superparamagnetic iron oxide nanoparticle, ferumoxytol, can be used as a contrast agent for magnetic resonance imaging (MRI) of brain vasculature, intracerebral tumors and neurological lesions. Although ferumoxytol is a blood pool agent immediately after infusion, we have shown that by 24h ferumoxytol leaks across the damaged blood-brain barrier in a rat model of acute neuroinflammation, where MRI signal changes correlated with nanoparticle uptake by macrophages, microglia and activated astrocytes. The purpose of this study was to test the hypothesis that delayed MRI would demonstrate uptake of ferumoxytol by inflammatory cells in and around the tumor in rat models of intracerebral metastasis. Immune-compromised nude rats received intracerebral implantation of human metastatic cancer cells including H460 non-small cell lung carcinoma and HCC1954 breast carcinoma. When brain tumors were >10mm3 volume, rats underwent baseline T1, T2, and T2* scans on the 11.75T Bruker MRI scanner, then received ferumoxytol 25 mg/kg IV. MRI scans were repeated 24h after ferumoxytol, and rat brains were immediately harvested for immunohistochemical analysis. Post-ferumoxytol T1-weighted scans showed pockets of hypointensity dispersed throughout the tumor and, occasionally, a distinct rim of signal dropout at the tumor border, combined with hyperintensity extending 1-2 mm around the tumor mass. Post-ferumoxytol T2-weighted scans showed mottled signal dropout throughout the tumor, while T2* scans showed intense hypointensity throughout the tumor mass extending into surrounding brain. Immunohistochemistry for the ferumoxytol coating showed intense staining in macrophages within necrotic areas of the tumor and dispersed staining in cells of astroglial morphology in peritumoral brain, but little to no staining within tumor cells. We conclude that delayed ferumoxytol MRI provides a biomarker of the inflammatory component of intracerebral tumors.
Efficacy of obesity in metastatic colorectal cancer patients treated with bevacizumab-based chemotherapy combinations: A Turkish Oncology Group Study
Authors: M. Artac, L. Korkmaz, H. Coskun, F. Dane, B. Karabulut, M. Karaağaç, D. Çabuk, S. Karabulut, F. Aykan, H. Doruk, N. Avci, S. Turhal
Journal: Annals of Oncology (2016)
Therapy of Myelodysplastic Syndrome (MDS) with Azacitidine Given in Combination with Etanercept: A Phase II Study.
Authors: Aaron L. Holsinger, Aravind Ramakrishnan, Barry Storer, Pamela S. Becker, Stephen Petersdorf, H. Joachim Deeg, Bart L. Scott
Journal: Blood (2007)
Noninvasive Treatments for Acute, Subacute, and Chronic Low Back Pain: A Clinical Practice Guideline From the American College of Physicians
Authors: Amir Qaseem, Timothy J. Wilt, Robert M. McLean, Mary Ann Forciea
Journal: Annals of Internal Medicine (2017)

The American College of Physicians (ACP) developed this guideline to present the evidence and provide clinical recommendations on noninvasive treatment of low back pain.Using the ACP grading system, the committee based these recommendations on a systematic review of randomized, controlled trials and systematic reviews published through April 2015 on noninvasive pharmacologic and nonpharmacologic treatments for low back pain. Updated searches were performed through November 2016. Clinical outcomes evaluated included reduction or elimination of low back pain, improvement in back-specific and overall function, improvement in health-related quality of life, reduction in work disability and return to work, global improvement, number of back pain episodes or time between episodes, patient satisfaction, and adverse effects.The target audience for this guideline includes all clinicians, and the target patient population includes adults with acute, subacute, or chronic low back pain.Given that most patients with acute or subacute low back pain improve over time regardless of treatment, clinicians and patients should select nonpharmacologic treatment with superficial heat (moderate-quality evidence), massage, acupuncture, or spinal manipulation (low-quality evidence). If pharmacologic treatment is desired, clinicians and patients should select nonsteroidal anti-inflammatory drugs or skeletal muscle relaxants (moderate-quality evidence). (Grade: strong recommendation).For patients with chronic low back pain, clinicians and patients should initially select nonpharmacologic treatment with exercise, multidisciplinary rehabilitation, acupuncture, mindfulness-based stress reduction (moderate-quality evidence), tai chi, yoga, motor control exercise, progressive relaxation, electromyography biofeedback, low-level laser therapy, operant therapy, cognitive behavioral therapy, or spinal manipulation (low-quality evidence). (Grade: strong recommendation).In patients with chronic low back pain who have had an inadequate response to nonpharmacologic therapy, clinicians and patients should consider pharmacologic treatment with nonsteroidal anti-inflammatory drugs as first-line therapy, or tramadol or duloxetine as second-line therapy. Clinicians should only consider opioids as an option in patients who have failed the aforementioned treatments and only if the potential benefits outweigh the risks for individual patients and after a discussion of known risks and realistic benefits with patients. (Grade: weak recommendation, moderate-quality evidence).
Hepatitis B reactivation in hepatitis B and C coinfected patients treated with antiviral agents: A systematic review and meta‐analysis
Authors: Guofeng Chen, Cheng Wang, Jing Chen, Dong Ji, Yudong Wang, Vanessa Wu, Johan Karlberg, George Lau
Journal: Hepatology (2017)

There is an increased awareness of hepatitis B (HBV) reactivation in chronic hepatitis C (CHC) patients coinfected with HBV treated with pan‐oral direct‐acting antiviral agents (DAAs). We performed a systematic review and meta‐analysis to compare the rate of HBV reactivation in CHC patients coinfected with overt HBV (hepatitis B surface antigen [HBsAg] positive) and occult HBV (HBsAg negative with positive HBV DNA) infection separately, treated with interferon (IFN)‐based therapy to those with pan‐oral DAAs. The primary outcome was HBV reactivation, and the secondary outcomes included hepatitis due to HBV reactivation, sustained virologic response (SVR) for CHC, loss of HBV DNA and HBsAg seroclearance. Although the pooled incidence rate of HBV reactivation, among CHC patients with overt HBV (n = 779), was similar among those treated with IFN‐based therapy (14.5%, P &lt; 0.001) and DAAs (12.2%, P = 0.03; P = 0.91 for heterogeneity between subgroups), it was reported to occur much earlier in those treated with DAAs (4‐12 weeks during treatment) than in those treated with IFN‐based therapies (most at the end of treatment and some during follow‐up). Also, studies with DAA‐based therapies were more likely to report incidence of hepatitis due to HBV reactivation (12.2% in DAAs vs. 0% in IFN; P = 0.009 for heterogeneity between subgroups). HBV reactivation and hepatitis due to HBV reactivation also occurred, though less frequently in CHC patients with occult HBV infection. CHC SVR was not affected by HBV reactivation ( P = 0.27). Conclusion: HBV reactivation occurs earlier and is clinically more significant in CHC patients coinfected with overt and occult HBV who are treated with pan‐oral DAAs compared with IFN‐based therapy. It is therefore important to have all patients screened for evidence of overt or occult HBV infection and managed during pan‐oral DAAs therapy. (H epatology 2017;66:13–26).
Transcend NHL 001: Immunotherapy with the CD19-Directed CAR T-Cell Product JCAR017 Results in High Complete Response Rates in Relapsed or Refractory B-Cell Non-Hodgkin Lymphoma
Authors: Jeremy S. Abramson, Lia Palomba, Leo I Gordon, Matthew Lunning, Jon Arnason, Andres Forero-Torres, Tina M. Albertson, Victoria Shaw Exton, Claire Sutherland, Benhuai Xie, Susan Snodgrass, Tanya Siddiqi
Journal: Blood (2016)
P13.13 Trans-endothelial migration of non-small cell lung cancer cells: Role of CD15 and CD15s in brain metastasis
Authors: S. A. Jassam, Z. Maherally, K. Ashkan, H. L. Fillmore, G. J. Pilkington
Journal: Neuro-Oncology (2016)

Introduction:
Metastatic non-small cell lung cancer represents the most common cause of brain metastasis in adults. Interaction between circulating cancer cells and brain endothelial cells play a key role in brain metastasis, but their underlining molecular mechanisms are still not fully understood. The CD15 and CD15s epitopes function as cell adhesion molecules and are known to be correlated with metastasis in non-CNS cancers. This study aims to investigate the role of CD15 and CD15s in cancer cell adhesion and trans-endothelial migration during metastasis to the brain by perturbing the expression of the fucosyltransferases responsible for the synthesis of these epitopes.
Prognostic significance of cytogenetic abnormalities in T‐cell prolymphocytic leukemia
Authors: Zhihong Hu, L. Jeffrey Medeiros, Lianghua Fang, Yi Sun, Zhenya Tang, Guilin Tang, Tsieh Sun, Andres E. Quesada, Shimin Hu, Sa A. Wang, Lin Pei, Xinyan Lu
Journal: American Journal of Hematology (2017)

T-cell prolymphocytic leukemia (T-PLL) is an aggressive mature T-cell neoplasm. The most common cytogenetic abnormality associated with T-PLL is inv(14)(q11.2q32) involving TCL1, but other abnormalities also have been reported. In this study, we correlated cytogenetic abnormalities with clinical outcome in 97 T-PLL patients, including 66 men and 31 women with a median age of 63 years (range, 34-81). Twenty-seven patients had a normal karyotype (NK), one had two chromosomal aberrations, and 69 had a complex karyotype (CK). Patients with a CK had poorer overall survival (OS) than patients with a NK (P = .0016). In the CK group, the most common aberrations involved 14q (n = 45) and 8q (n = 38). Additional deletions of chromosomes 17p, 11q, 6q, 12p, 13q were observed frequently. No individual cytogenetic abnormality impacted OS. Patients with ≥5 aberrations had an OS of 11 months versus 22 months in patients with <5 aberrations (P = 0.0132). Fluorescence in situ hybridization for TCL1 successfully performed in 27 cases showed rearrangement in 8/10 (80%) NK versus 16/17 (94%) CK cases. OS of patients with TCL1 rearrangement and/or 14q aberrations was not significantly different from patients without TCL1 rearrangement and 14q aberrations (P = .3467). Patients with refractory disease showed worse OS in both the NK and CK groups (P = .0014 and P < .0001, respectively), compared with patients who achieved remission but then relapsed. Stem cell transplantation did not appear to improve OS regardless of karyotype complexity. In conclusion, patients with T-PLL often have a CK which is a poor prognostic factor, particularly in patients with ≥5 cytogenetic aberrations.
Phase II trial of the PI3 kinase inhibitor BKM120 with or without enzalutamide in men with metastatic castration resistant prostate cancer (mCRPC).
Authors: Andrew J. Armstrong, Susan Halabi, Patrick Healy, Joshi J. Alumkal, Evan Y. Yu, Carolyn Winters, Carey Hobbs, Colleen Soleau, Rachel Slottke, Kelly Mundy, Daniel J. George
Journal: Journal of Clinical Oncology (2015)

5025 Background: PI3K pathway activation is common in mCRPC. BKM120 (buparlisib) is an oral, pan-class I PI3 kinase inhibitor. Preclinical data demonstrated a reciprocal feedback loop between PI3K and androgen receptor (AR) signaling; thus, we evaluated the efficacy of BKM120 in men with heavily pre-treated mCRPC including those progressing on enzalutamide (E). Methods: This was a 3 site phase 2 Dept of Defense Prostate Cancer Clinical Trials Consortium open-label trial of BKM120 100 mg once daily with ongoing ADT in men with mCRPC who had failed or were not candidates for docetaxel. Continuation of E was permitted in men progressing on E with subsequent addition of BKM120. The primary endpoint was the rate of composite of radiographic and clinical PFS at 6 months with a goal of 40% vs. a historic rate 25% using a two-stage design with interim futility analysis. Results: Thirty men were accrued: 63% post-docetaxel; median PSA was 70 ng/dl, 83% had > 4 prior therapies for CRPC; 43% men received concurrent E. The trial met criteria for futility, with a 6 month PFS rate of 10% (95% CI 2.5-23.6%). Median composite PFS was 1.9 months (95% CI: 1.8, 3.4) and 3.5 months (95% CI 1.2, 5.5) with concurrent E. Median OS was 11 months (95% CI 4.8, 14.4). E did not appear to increase the BKM120 side effect profile. The PSA decline proportion was 23%, but no patients achieved a > 50% decline, with median PSA change of +39%. No objective responses were observed. Related SAEs occurred in 3 men including respiratory infection and organ failure (1), urinary tract obstruction due to local progression (1), and severe confusion (1). One seizure was observed in a man who was found to have a new CNS metastasis during concurrent BKM120/E therapy. Grade 3 related AEs were seen in 47% of patients, with 10% stopping BKM120 due to toxicity. The most common related AEs included grade 1-2 weight loss, diarrhea, nausea, fatigue, anorexia, rash, hyperglycemia, and anxiety and mood disorders. Conclusions: BKM120 did not improve PFS over historic control data in men with mCRPC, either alone or when added to AR inhibition in men progressing on enzalutamide. These data suggest that PI3K inhibition is not sufficient to block mCRPC progression. Clinical trial information: NCT01385293.
Doctor is allowed to practise again as reinstatement becomes less rare
Authors: Clare Dyer
Journal: BMJ (2017)

A doctor struck off in 2007 for dishonesty has been allowed back on to the UK medical register by a medical practitioners’ tribunal despite opposition from the General Medical Council.

Reinstatement remains a rare event but not quite as rare as it once was. Christopher Lamming becomes the third doctor in nine months to be returned to the register after being struck off for disciplinary reasons. In the six years from the beginning of 2011 to the end of 2016 only 10 doctors were restored to the register, while 42 had one or more applications for reinstatement …