HPV-positive/p16-positive/EBV-negative nasopharyngeal carcinoma in white North Americans

Background Human papillomavirus (HPV) has been detected in keratinizing nasopharyngeal carcinomas (NPCs); however, the relationship between HPV and Epstein–Barr virus (EBV) among whites with nonkeratinizing NPCs remains unclear. The HPV, p16, and EBV status was examined in current University of Michigan patients with NPC. Methods From 2003 to 2007, 89 patients, 84 with oropharyngeal cancer (OPC) and 5 with NPC, were enrolled in an organ-sparing trial. Biopsy tissues from all 89 patients were evaluated for HPV and p16 expression. A separate HPV analysis of the 84 OPC patients is in progress. Among the patients with NPC, tumor tissue was also analyzed for EBV-encoded RNA (EBER). Results Five of 89 patients (5.6%) had NPC, all with nonkeratinizing histology. The 4 white patients with NPC were HPV(+) (subtype-16, subtype-18 [2 patients], and subtype-59)/p16(+)/EBER(-). One Asian patient with NPC had an HPV(-)/p16(-)/EBER(+) NPC tumor that developed distant metastases. Conclusion We postulate that HPV may be the etiologic factor in some EBV-negative, nonkeratinizing NPCs among whites. © 2009 Wiley Periodicals, Inc. Head Neck, 2010Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/71364/1/21216_ftp.pd

Head and neck squamous cell carcinoma of unknown primary: Neck dissection and radiotherapy or definitive radiotherapy

Background Management of head and neck carcinoma from unknown primary (HNCUP) remains controversial, with neck dissection and radiotherapy (RT) or definitive RT both commonly used. The purpose of this study was to characterize HNCUP and retrospectively compare outcomes for patients treated with neck dissection + RT versus definitive RT. Methods From 1994 to 2009, 41 patients with HNCUP underwent either neck dissection + RT ( n  = 22) or definitive RT ± concurrent chemotherapy ( n  = 19) at our institution. Treatment outcomes were compared using Kaplan–Meier methods and log‐rank test. Results There were no differences between patients treated with neck dissection + RT and definitive RT in overall survival (OS), progression‐free survival (PFS), locoregional relapse‐free survival (LRFS), freedom from locoregional failure (FFLRG), or freedom from distant failure (FFDF). Among 17 patients who underwent neck dissection + RT for whom human papillomavirus (HPV) status could be determined, HPV(+) patients trended toward improved OS ( p  = .06) and PFS ( p  = .15). Conclusion Neck dissection and postoperative RT resulted in similar outcomes as definitive RT. The prognostic implications of HPV(+) nodes in HNCUP are similar to those in oropharyngeal primary cancers. © 2013 Wiley Periodicals, Inc. Head Neck 36: 1589–1595, 2014Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/109313/1/hed23479.pd

A randomized, phase II study of sequential belimumab and rituximab in primary Sjögren's syndrome

BACKGROUND. Primary Sjögren's syndrome (pSS) is characterized by B cell hyperactivity and elevated B-lymphocyte stimulator (BLyS). Anti-BLyS treatment (e.g., belimumab) increases peripheral memory B cells; decreases naive, activated, and plasma B cell subsets; and increases stringency on B cell selection during reconstitution. Anti-CD20 therapeutics (e.g., rituximab) bind and deplete CD20-expressing B cells in circulation but are less effective in depleting tissue-resident CD20+ B cells. Combined, these 2 mechanisms may achieve synergistic effects. METHODS. This 68-week, phase II, double-blind study (GSK study 201842) randomized 86 adult patients with active pSS to 1 of 4 arms: placebo, s.c. belimumab, i.v. rituximab, or sequential belimumab + rituximab. RESULTS. Overall, 60 patients completed treatment and follow-up until week 68. The incidence of adverse events (AEs) and drug-related AEs was similar across groups. Infections/infestations were the most common AEs, and no serious infections of special interest occurred. Near-complete depletion of minor salivary gland CD20+ B cells and a greater and more sustained depletion of peripheral CD19+ B cells were observed with belimumab + rituximab versus monotherapies. With belimumab + rituximab, reconstitution of peripheral B cells occurred, but it was delayed compared with rituximab. At week 68, mean (± standard error) total EULAR Sjögren's syndrome disease activity index scores decreased from 11.0 (1.17) at baseline to 5.0 (1.27) for belimumab + rituximab and 10.4 (1.36) to 8.6 (1.57) for placebo. CONCLUSION. The safety profile of belimumab + rituximab in pSS was consistent with the monotherapies. Belimumab + rituximab induced enhanced salivary gland B cell depletion relative to the monotherapies, potentially leading to improved clinical outcomes

A randomized, phase II study of sequential belimumab and rituximab in primary Sjögren's syndrome

BACKGROUND: Primary Sjögren’s syndrome (pSS) is characterized by B cell hyperactivity and elevated B-lymphocyte stimulator (BLyS). Anti-BLyS treatment (e.g., belimumab) increases peripheral memory B cells; decreases naive, activated, and plasma B cell subsets; and increases stringency on B cell selection during reconstitution. Anti-CD20 therapeutics (e.g., rituximab) bind and deplete CD20-expressing B cells in circulation but are less effective in depleting tissue-resident CD20(+) B cells. Combined, these 2 mechanisms may achieve synergistic effects. METHODS: This 68-week, phase II, double-blind study (GSK study 201842) randomized 86 adult patients with active pSS to 1 of 4 arms: placebo, s.c. belimumab, i.v. rituximab, or sequential belimumab + rituximab. RESULTS: Overall, 60 patients completed treatment and follow-up until week 68. The incidence of adverse events (AEs) and drug-related AEs was similar across groups. Infections/infestations were the most common AEs, and no serious infections of special interest occurred. Near-complete depletion of minor salivary gland CD20(+) B cells and a greater and more sustained depletion of peripheral CD19(+) B cells were observed with belimumab + rituximab versus monotherapies. With belimumab + rituximab, reconstitution of peripheral B cells occurred, but it was delayed compared with rituximab. At week 68, mean (± standard error) total EULAR Sjögren’s syndrome disease activity index scores decreased from 11.0 (1.17) at baseline to 5.0 (1.27) for belimumab + rituximab and 10.4 (1.36) to 8.6 (1.57) for placebo. CONCLUSION: The safety profile of belimumab + rituximab in pSS was consistent with the monotherapies. Belimumab + rituximab induced enhanced salivary gland B cell depletion relative to the monotherapies, potentially leading to improved clinical outcomes. TRIAL REGISTRATION: ClinicalTrials.gov NCT02631538. FUNDING: Funding was provided by GSK

The effect of 24-week belimumab treatment withdrawal followed by treatment restart in patients with SLE: an open-label, non-randomised 52-week study

Abstract Background Treatment goals for patients with systemic lupus erythematosus (SLE) include minimising disease activity and reducing the risk of flares. Although belimumab is effective at reducing disease activity and risk of severe flares, it was previously unknown what the clinical effects were upon treatment discontinuation. The objective of this study was to assess the impact of temporary withdrawal of intravenous (IV) belimumab in patients with SLE. Methods This multicentre, open-label, non-randomised, 52-week study (GSK Study BEL116027; NCT02119156) recruited patients with SLE and stable low disease activity, of whom those on belimumab 10 mg/kg IV plus standard therapy either discontinued belimumab for 24 weeks and then restarted belimumab 10 mg/kg IV every 4 weeks (q4w) for 28 weeks (treatment holiday [TH] group), or continued on belimumab 10 mg/kg IV plus standard therapy q4w for 52 weeks (treatment continuation [TC] group). The primary endpoint was median time to first Safety of Estrogens in Lupus Erythematosus National Assessment-SLE Disease Activity Index (SELENA-SLEDAI) Flare Index flare. Secondary and other endpoints included rate of any flare, time to severe flare, time to renal flare and rebound (SELENA-SLEDAI score exceeding parent study baseline). Data on rebound phenomenon in patients with any disease level of SLE who had permanently withdrawn from further belimumab treatment (long-term discontinuation group [LTD]) were also assessed. Safety was assessed. Results The primary endpoint was not evaluable in the TH (n = 12) and TC (n = 29) groups as fewer than half of patients flared. Unadjusted flare rates per patient-year were 1.0 during treatment discontinuation and 0.3 during treatment restart (0.6 overall) in the TH group and 0.6 in the TC group; there were no severe or renal flares. No TH patients rebounded; 2 (6.9%) TC patients rebounded; 2 (5.1%) patients in the LTD group rebounded. There were no new safety signals. Conclusions Twenty-four-week belimumab discontinuation did not appear to increase the risk of flares or rebound in patients with low SLE disease activity; flare rates were low in both groups. Further studies may help to fully determine the effect of belimumab discontinuation. Trial registration ClinicalTrials.gov, NCT02119156 . Registered on April 21, 2014

Building a similarity engine

Thesis: M. Eng., Massachusetts Institute of Technology, Department of Electrical Engineering and Computer Science, 2018.This electronic version was submitted by the student author. The certified thesis is available in the Institute Archives and Special Collections.Cataloged from student-submitted PDF version of thesis.Includes bibliographical references (page 53).In the seventeenth century, Philosophers such as Leibniz and Descartes put forward proposal for codes to relate words between languages. The first patents for "translating machines" were applied for in the mid-1930s. Up to the 1980s, most Natural Language Processing (NLP) systems were based on complex sets of hand-written rules. At that time however, the introduction of machine learning algorithms for language processing revolutionized NLP.[5] In 2008, Collobert and Weston exhibited the power of pre-trained word embed- dings in a paper called A unified architecture for natural language processing. Here, word embeddings is highlight for its ability in downstream tasks. They also discuss a neural network architecture that many of todays approaches are built upon. In 2013, Mikolov created word2vec, a toolkit that enabled the training and use of pre-trained embeddings. In 2014, Pennington introduced GloVe, a competitive set of pre-trained embeddings. Starting off, a single word or group of words can be converted into a vector. This vector can be created using the Skip gram method, which predicts the possible words nearby, the LSTM-RNN method, which forms semantic representations of sentences by learning more about the sentence as it iterates through a sentence, using single convolution neural networks, and several other methods. Using these theories, we are trying to build a Similarity Engine which provides machine learning based content search and classification of data.by Nikhil Narendra Punwaney.M. Eng