tbuckley/cabot-search huggingface dataset:
Hepatitis B reactivation in patients with solid tumors: A systematic review and meta-analysis.
Authors: Lisa K. Hicks, Jordan J. Feld, Ronak Saluja, Judy Truong, Adam E. Haynes, Kelvin K. Chan
Journal: Journal of Clinical Oncology (2016)

138 Background: Hepatitis B virus (HBV) affects over 250 million people worldwide. Most people with chronic HBV (HBsAg positive) have no signs or symptoms of infection. However, when exposed to immunosuppression they are at risk of HBV reactivation which can cause hepatitis, liver failure and death. The risk of HBV reactivation in patients receiving chemotherapy for solid tumors, the efficacy of antiviral prophylaxis, and the clinical impact of HBV reactivation in this setting are uncertain. Primary Aim: To estimate the risk of clinical HBV reactivation (increased HBV DNA + transaminitis) among HBsAg-positive patients administered chemotherapy for a solid tumor. Secondary Aims: To estimate the efficacy of anti-viral prophylaxis and the risk of death from HBV reactivation in patients receiving chemotherapy for solid tumors. Methods: A systematic review and meta-analysis of the English language literature on HBV reactivation was completed (OVID Medline, 1946 to Aug 2013). All citations were reviewed by two or more authors. Data from patients with hematologic malignancies were excluded. Pooled probabilities of HBV reactivation risk, death from HBV reactivation, and odds ratio for the impact of anti-viral prophylaxis were estimated with a random effects model. Results: 2,667 citations were identified; 19 were eligible for inclusion. The pooled estimate for clinical HBV reactivation in HBsAg-positive patients receiving chemotherapy for a solid tumor was 21.9% (95% CI; 16.5% to 27.3%) in those not receiving anti-viral prophylaxis, and 2.4% (95% CI 0.7% to 4.2%) in those receiving anti-viral prophylaxis. The odds ratio for clinical HBV reactivation with antiviral prophylaxis compared to no prophylaxis was 0.12 (95% CI 0.06 to 0.25). In the absence of viral prophylaxis, the risk of dying from HBV reactivation in HBsAg-positive solid tumor patients was estimated at 1.3% with a 95% CI of 0.3% to 2.3%. Conclusions: Patients with chronic HBV who are administered chemotherapy for a solid tumor appear to be at substantial risk of clinical HBV reactivation; this risk may be mitigated by anti-viral prophylaxis. In the absence of anti-viral therapy, patients may experience a small but important risk of dying from HBV reactivation.
A Truncated IL‐17RC Peptide Ameliorates Synovitis and Bone Destruction of Arthritic Mice
Authors: Yuxuan Du, Yulong Tong, Wentong Mei, Junhui Jia, Menglin Niu, Wei Cao, Weiwei Lou, Shentao Li, Zhanguo Li, W. Alexander Stinson, Huihui Yuan, Wenming Zhao
Journal: Advanced Healthcare Materials (2016)

Peptide‐based therapy, such as modified peptides, has attracted increased attention. IL‐17 is a promising therapeutic target for autoimmune diseases, and levels of circulating bioactive IL‐17 are associated with rheumatoid arthritis severity. In this study, a modified truncated IL‐17RC is generated to ameliorate inflammation and bone destruction in arthritis. The truncated IL‐17RC binds to both IL‐17A and IL‐17F with higher binding capacity compared to nonmodified IL‐17RC. In addition, the truncated IL‐17RC reduces the secretion of inflammatory and osteoclastogenic factors induced by IL‐17A/F in vitro. Moreover, the administration of truncated IL‐17RC dramatically improves symptoms of inflammation and inhibited bone destruction in collagen‐induced arthritis mice. Collectively, these data demonstrate that modified truncated IL‐17RC peptide may be a more effective treatment strategy in the simultaneous inhibition of both IL‐17A and IL‐17F signaling, whereas the existing agents neutralize IL‐17A or IL‐17F alone. These suggest that the truncated IL‐17RC may be a potential candidate in the treatment of inflammatory associated bone diseases.
Abstract 3324: A novel role for PAK4 in the regulation of EMT and stemness in glioblastoma
Authors: Divya Kesanakurti, Jihong Xu, Rao S. Jasti, Vinay K. Puduvalli
Journal: Cancer Research (2015)

Abstract Glioblastomas (GB) are the most aggressive of primary brain tumors with high rates of tumor recurrence and poor prognosis. Epithelial-mesenchymal transition (EMT) is the dynamic transdifferentiation process which leads to acquisition of invasiveness, stem-like characteristics and drug resistance in tumor cells. A small fraction of radio- and chemo-resistant cancer stem cells (CSC) with a capacity of self-renewal is considered to be crucial for tumor recurrence. Our previous studies indicated high levels of expression of p21-activated kinase 4 (PAK4) in GBs and confirmed its role in the regulation of proliferation, migration and invasion. Here, we aimed to determine whether PAK4-regulated invasiveness was associated with mesenchymal transition of glioma cells and to delineate the essential signaling events that governed EMT and maintenance of stemness in GBs. PAK4 overexpression in glioma cells resulted in loss of E-cadherin and Zo-1 and a significant increase in N-cadherin and vimentin levels. Conversely, shRNA-mediated PAK4 downregulation led to loss of mesenchymal phenotype and markers in glioma cell lines. Further, irradiation (IR, 8 Gy) treatments significantly elevated PAK4 expression and nuclear localization in correlation with increased EMT in glioma cells. FACS analysis and western blotting indicated an enrichment of CD133+ CSCs with high expression of CD133 and Nestin in IR-treated cells. In order to study the significance IR-induced EMT and stemness with PAK4 nuclear translocation, we performed a transcription factor (TF) interaction array with immunoprecipitated PAK4 as bait, which revealed nuclear-PAK4 association with PPARγ and other TFs. Moreover, immunoprecipitation, ChIP and re-ChIP experiments showed IR-induced PAK4 binding with PPARγ nuclear receptor complex and recruitment on the PPREs of NADPH oxidase-1 promoter and elevated Nox1 expression in IR-treated cells. PAK4-knockdown suppressed the IR-induced EMT and stemness in the glioma cells lines. In line with these in vitro results, mouse orthotopic intracranial xenograft experiments showed decreased tumor growth and N-cadherin expression in tumors from PAK4-shRNA expressing cells when compared with controls. These results strongly support a role for PAK4 in the regulation of IR-induced EMT and stemness via PPARγ/Nox1 signaling and provide a rationale for PAK4 as a new therapeutic target against glioblastoma and suggest a potential for overcoming radioresistance in these tumors. Citation Format: Divya Kesanakurti, Jihong Xu, Rao S. Jasti, Vinay K. Puduvalli. A novel role for PAK4 in the regulation of EMT and stemness in glioblastoma. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 3324. doi:10.1158/1538-7445.AM2015-3324
Targeting CAG repeat RNAs reduces Huntington’s disease phenotype independently of huntingtin levels
Authors: Laura Rué, Mónica Bañez-Coronel, Jordi Creus-Muncunill, Albert Giralt, Rafael Alcalá-Vida, Gartze Mentxaka, Birgit Kagerbauer, M. Teresa Zomeño-Abellán, Zeus Aranda, Veronica Venturi, Esther Pérez-Navarro, Xavier Estivill, Eulàlia Martí
Journal: Journal of Clinical Investigation (2016)

Huntington's disease (HD) is a polyglutamine disorder caused by a CAG expansion in the Huntingtin (HTT) gene exon 1. This expansion encodes a mutant protein whose abnormal function is traditionally associated with HD pathogenesis; however, recent evidence has also linked HD pathogenesis to RNA stable hairpins formed by the mutant HTT expansion. Here, we have shown that a locked nucleic acid-modified antisense oligonucleotide complementary to the CAG repeat (LNA-CTG) preferentially binds to mutant HTT without affecting HTT mRNA or protein levels. LNA-CTGs produced rapid and sustained improvement of motor deficits in an R6/2 mouse HD model that was paralleled by persistent binding of LNA-CTG to the expanded HTT exon 1 transgene. Motor improvement was accompanied by a pronounced recovery in the levels of several striatal neuronal markers severely impaired in R6/2 mice. Furthermore, in R6/2 mice, LNA-CTG blocked several pathogenic mechanisms caused by expanded CAG RNA, including small RNA toxicity and decreased Rn45s expression levels. These results suggest that LNA-CTGs promote neuroprotection by blocking the detrimental activity of CAG repeats within HTT mRNA. The present data emphasize the relevance of expanded CAG RNA to HD pathogenesis, indicate that inhibition of HTT expression is not required to reverse motor deficits, and further suggest a therapeutic potential for LNA-CTG in polyglutamine disorders.
Initial compared to deferred cytoreductive nephrectomy for metastatic kidney cancer and its association with improved survival in the targeted therapy era.
Authors: Liam Connor Macleod, Scott S. Tykodi, Sarah Holt, John L. Gore
Journal: Journal of Clinical Oncology (2016)

607 Background: Since 2005 seven new agents were approved for metastatic renal cell carcinoma (mRCC), demarcating a transition from the cytokine to the targeted therapy era. Trials demonstrated a survival benefit for upfront cytoreductive nephrectomy (CN) pre-2005. However, upfront versus delayed CN relative to targeted therapy has not been reported in the trial arena. We hypothesized that upfront CN confers a survival benefit in the targeted therapy era. We analyze survival in a population based cohort exposed to targeted therapies with upfront CN compared to deferred CN. Methods: Patients from SEER registries (2005-2011) with mRCC were categorized into: 1.) CN followed by targeted therapy or 2). initial targeted therapy. Additional exclusions were age &lt; 66, due to chance of uncaptured non-Medicare care, competing non-renal stage IV cancer and non-clear cell histology. Targeted therapy was identified from Medicare Part D files (bevacizumab, sunitinib, sorafenib, axitinib, pazopanib, temsirolmus, everolimus) and duration of use. Clinical data, including co-morbidities, were obtained from Medicare inpatient and outpatient files, and cancer data from Medicare-linked SEER files. Unadjusted and multivariable Cox proportional hazards regression determined association between survival in the two groups. Propensity matching with bootstrapping was performed to control for measurable confounding in treatment selection. Results: Of 1,326 mRCC cases screened, 491 met the inclusion criteria. Median survival in the initial CN group (N = 194) was 20 months (IQR 12-32) compared to 14 months (IQR 6-27) in the initial targeted therapy group (N = 297, p &lt; 0.01). On multivariable analysis upfront CN was associated with improved survival (HR 0.57 95% CI 0.44, 0.74). On propensity matched analysis the survival advantage (average treatment effect on the treated, ATT) for upfront CN was 7.4 months (95% CI 3.86, 11.21). Conclusions: This study population closely resembles the treatment groups in ongoing randomized trials on the surgical management of mRCC in the targeted therapy era and demonstrates a survival advantage for upfront CN.
Randomized phase 2 trial of ixazomib and dexamethasone in relapsed multiple myeloma not refractory to bortezomib
Authors: Shaji K. Kumar, Betsy R. LaPlant, Craig B. Reeder, Vivek Roy, Alese E. Halvorson, Francis Buadi, Morie A. Gertz, P. Leif Bergsagel, Angela Dispenzieri, Melanie A. Thompson, Jamie Crawley, Prashant Kapoor, Joseph Mikhael, Keith Stewart, Suzanne R. Hayman, Yi L. Hwa, Wilson Gonsalves, Thomas E. Witzig, Sikander Ailawadhi, David Dingli, Ronald S. Go, Yi Lin, Candido E. Rivera, S. Vincent Rajkumar, Martha Q. Lacy
Journal: Blood (2016)
Limitation of the Gail score and mammographic density in recruiting candidate for prevention of breast cancer in high-risk women with precancerous lesions
Authors: D. Rosner, A. Meschcheryakov, V. Bogatyrev, V. Sokolova, A. Hutson, G. Korzhenkova, J. Yeh, M. Davydov
Journal: Journal of Clinical Oncology (2008)

1548 Background: The purpose of our ongoing prospective Breast Cancer (BC) Prevention Trial using chemoprevention in high-risk women with precancerous lesions, hyperplasia usual type (HUT) or atypical hyperplasia (AH) was to refine the methodology in recruiting more accurately the candidates. Methods: A total of 282 postmenopausal women following conventional first risk assessment were entered in an ongoing prospective trial, in a single institution, N.N. Blokhin Cancer Research Center, Moscow, Russia from 10/2005 to 11/2007. Following prior biopsies for HUT or AH patients were measured for Gail Score (GS) and mammographic density (MD). Results: Following fine needle aspiration biopsy (FNAB) 149 patients were classified into five categories. The FNAB cell number count is described in terms of the median (range) and proportion of cells (POC) >3000 (95% confidence interval). The results follow: Category 1: HUT, ER(+), 29 patients, median=3,427 (2,200–5,626), POC=0.57 (0.42, 0.72); Category 2: AH, ER(+), 41 patients, median=5,790 (4,550–7,100), POC=0.81 (0.69, 0.90); Category 3: HUT, ER(-), 29 patients, median=1,500 (1,277–2,640), POC=0.28 (0.15, 0.45); Category 4: AH, ER(-), 26 patients, median=4,850 (3,160–6,160), POC=0.65 (0.50, 0.79); Category 5: Non-Proliferative, 24 patients, median=95 (45–299), POC=0.0 (0.0, 0.09). When the results of proliferative and non-proliferative cytology were analyzed with GS<1.67, 45% of the cases would be excluded from the therapy. Furthermore, 46% of cases with GS > 1.67 with non-proliferative cytology would be included in chemoprevention studies in absence of proliferative disease. What was important for us was to have accurate readings of breast density and recognize the presence of precancer (HUT or AH) and to arrest or reverse premalignant lesions. Conclusions: The presence of cytomorphology of HUT or AH obtained FNAB in high-risk patients for breast cancer would allow more accurate selection of candidates for chemoprevention than GS model and breast density, which can substantially under- or overestimate precancerous lesions. A series of patients with increased MD would receive unnecessary prophylactic therapy in the absence of precancerous lesions. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration Novartis
Clearance and Genetic Variability of Von Willebrand Factor Are Major Determinants of the Pharmacokinetic Behavior of Factor VIII Concentrates in the Treatment of Pediatric Hemophilia A
Authors: Kenichi Ogiwara, Laura L Swystun, Ilinca Georgescu, Christine Brown, Angie Tuttle, Shawn Tinlin, Jayne Leggo, Silvia Albánez, Manuel Carcao, Victor S. Blanchette, Christoph Male, Katharina Thom, David Lillicrap
Journal: Blood (2014)
Innovations: Randomized phase II trial of erlotinib (E)/bevacizumab (B) compared with cisplatin (P)/gemcitabine (G) plus B in first-line treatment of advanced nonsquamous (NS) non-small cell lung cancer (NSCLC).
Authors: M. Thomas, A. Reuss, J. R. Fischer, S. Andreas, C. Kortsik, C. Grah, M. H. Serke, M. von Eiff, C. Witt, J. Kollmeier, E. Müller, L. Müller, M. Schenk, R. Heine, D. M. Behringer, M. Schroeder, N. Reinmuth, P. Schnabel, T. Acker, M. Wolf
Journal: Journal of Clinical Oncology (2011)

7504 Background: Combining EGFR kinase inhibition (E) with an anti-VEGF strategy (B) showed promising activity (RR 20%; PFS 6.2 months) in recurrent NS-NSCLC (J Clin Oncol (2005) 23: 2544). To assess feasibility and efficacy in the first-line setting E + B was compared with P/G+B in cisplatin eligible patients (pts). Methods: Stage IIIB/IV pts. were randomized on E (150 mg/daily) / B (15 mg/kg d1, q d 22) until progressive disease (PD) or P (80 mg/m2 d1, q d22) / G (1250 mg/m2 d1, q d22) up to 6 cycles+ B (15 mg/kg d1, q d 22) until PD. Primary end point was PFS in both arms. Results: 224 patients were randomized (EB, 111 / PGB, 113). Baseline characteristics were well balanced: age (median; range) 62.5; 39.5-84.6 / 59.9; 35.7-83.0; female 43%/44%; ECOG 0 – 1 – 2, 43% - 55% - 2% / 47% - 50% - 4%; never smoker – light former smoker – former smoker – smoker - missing 18.9% - 1.8% - 46.9% - 28.8% - 3.6% / 16.8% - 5.3% - 40.7% - 32.7% - 4.4%;histology: adenocarcinoma 85.6%/92.0%, large cell carcinoma 3.6%/2.7%, other 9.0%/4.4%, missing 1.8%/0.9%; EGFR mutation analysis available in 161 pts (71.9%/71.2%): wild-type (wt) 53.2%/62.0%, del 19 3.6%/1.8%, L858R 4.5%/2.7%, further mutations 9.0%/7.1%. Treatment conduction: E, duration in weeks 12.6; number of cycles (median) B, 5.0 / P, 5.5; G, 6.0; B, 4.0. Toxicity: hematologic grade 3 6.5%/27.3%; grade 4 0.9%/27.3%; non-hematologic grade 3 34.3%/34.6%; grade 4 9.3%/24.6%; treatment related mortality 4.6%/4.6%. Conclusions: PGB showed significant superiority to EB for RR (p < 0.0001) as well as PFS (HR = 0.6 [95%-CI 0.44-0.82], p = 0.0006) and favoured OS (HR = 0.73 [95%-CI 0.50-1.06], p = 0.1). EGFR mutations identify pts most likely to benefit from EB. Further biomarker exploitation is performed. Treatment N RR (%) PFS OS Median (mo) 95%-CI (%) Median (mo) 95% CI (%) EB Total 111 12.6 3.7 2.8-4.3 12.6 10.3-16.2 EGFR eval. 79 12.7 3.8 2.8-4.5 12.6 9.1-17.7 EGFR-mut 20 25.0 4.4 2.1-8.3 16.9 10.3-24.0 EGFR-wt 59 8.5 3.5 2.5-4.4 10.3 8.0- – PGB Total 113 33.6 7.2 6.0-8.9 15.7 11.9-21.7 EGFR eval. 82 35.4 7.3 5.9-9.5 15.0 11.9-29.2 EGFR-mut 12 16.7 5.7 2.8-8.4 10.0 6.0-19.8 EGFR-wt 70 38.6 8.1 6.5-9.7 18.1 12.0- –
Infusions of HSV-TK genetically modified donor lymphocytes enable a wider use of partially mismatched allogeneic transplantation by reducing infection related mortality and improving survival in high risk acute leukemia
Authors: F. Ciceri, C. Bonini, M. Lupo Stanghellini, A. Santoro, S. Slavin, J. Apperley, P. Bruzzi, S. Toma, C. Gallo Stampino, M. Bregni, C. Bordignon
Journal: Journal of Clinical Oncology (2006)

6519 Background: Allogeneic transplantation from a haploidentical family donor (haplo-SCT) represents the ideal solution to offer to every and each patient with high risk leukemia the potential cure of allogeneic adoptive immunotherapy. However, the delayed immune reconstitution compromise haplo-SCT with a high rate of late mortality and relapse. Methods: In a phase II multicenter trial (MM TK007), we explored early add-backs of donor lymphocytes genetically engineered to express the herpes simplex thymidine kinase (TK-DLI) suicide gene after haplo-SCT, in inducing early immune reconstitution and selective control of GvHD by ganciclovir. Results: Thirty-one advanced age pts (median age 51, 17–64) were transplanted for high risk leukemia. No immune reconstitution and no graft versus host disease (GvHD) were observed in absence of TK-DLI. 17 pts received TK-DLI at a median dose of 10 7 /kg with 1st infusion at d +42; 14 pts obtained a prompt and sustained immune reconstitution with CD3+ &gt;100/mcl at a median time of 86 d (57–127) from SCT and 21 d (13–42) from TK-DLI. Six pts developed acute (GvHD), (grade I to IV) that was always completely abrogated by ganciclovir. In patients in remission of leukemia at time of SCT, who were alive at day +42 and received TK-DLI, overall survival was 65% at 2 years (intention-to-treat analysis: 46%).The cumulative incidence of TRM and relapse showed a 40% probability of mortality with a median time of death of 90 days and last event at day +166. The cumulative infectious mortality beyond day 100 post transplant was 12.5% in our population, versus 53% of historical data. These data correlate with rapid development of normalization of the T cell repertoire documented by spectratype, followed by detection of high frequencies of T cells specific for CMV and EBV by gIFN ELISpot. Conclusions: These results indicate that TK-DLI drastically reduces late mortality after CD34+ haplo-SCT in adults. Survival rates in patients treated with TK-DLI were superior to survivals of haploidentical SCT of EBMT registry database. A phase III randomized multicentric study will start in 2006 to validate prospectively the advantage of TK-DLI in haplo-SCT. [Table: see text]
Cetuximab given every 2 weeks (q2w) plus irinotecan, as feasible option, for previously treated patients (pts) with metastatic colorectal cancer (MCRC)
Authors: J. Roca, V. Alonso, C. Pericay, P. Escudero, C. Grande, P. Vicente, A. Arrivi, C. Martin, I. Moreno, A. Garcia
Journal: Journal of Clinical Oncology (2008)

15122 Background: Cetuximab is an IgG1 monoclonal antibody targeting the EGFR, active in MCRC pts with a favorable safety profile. However weekly (q1w) administration would not be so convenient for chemotherapy regimens administered every 2 weeks. Based on similar pharmacokinetic, pharmacodynamic and safety results of cetuximab q1w and q2w dosing regimens (Ciardiello ECCO 2007), data arising recently from single-institutions have also shown similar efficacy of q2w regimen (Pfeiffer ASCO 2007; Martín- Martorell ECLU 2007). In the present study, we aimed to gather larger and more reliable data based on multiple institution experience. Methods: 126 pts from 19 Spanish sites were included from July 2006 to July 2007 in this prospective multicentre non-controlled study. Irinotecan-refractory MCRC pts with Karnofsky ≥70 received cetuximab 500 mg/m2 q2w plus irinotecan 180 mg/m2 q2w until PD or unacceptable toxicity. Primary endpoint was the progression-free survival (PFS) rate at 12 weeks (expected rate 50% ± 9%). Results: Median age 65 years (range 35–85); colon/rectum 70%/30%; karnofsky status ≤80%/≥90% in 45,5%/55,5% of patients; 66% pts were male. Main grade 3–4 toxicities were: neutropenia 3% (1% febrile neutropenia), diarrhea 14%, asthenia 7%, and acne like-rash 10% (45% G1–2). No G3–4 infusional or allergic reactions have been reported up to date. 40 of 106 pts currently evaluable for efficacy achieved DC (disease control) at 12 weeks, resulting in a PFS rate at 12 weeks of 43% (95% CI: 33%-53%). Conclusions: The preliminary PFS rate at 12w observed in this population met the protocol hypothesis for this study and confirms in a wider setting that cetuximab q2w plus irinotecan is an option as active and safe as the standard weekly regimen (Cunningham NEJM 2004). No significant financial relationships to disclose.
Prescription Trends—Brand-name Drugs vs Generic
Authors: Mark Chee, Samantha Ngooi, Vineet M. Arora
Journal: JAMA Internal Medicine (2016)

Our website uses cookies to enhance your experience. By continuing to use our site, or clicking "Continue," you are agreeing to our Cookie Policy | Continue JAMA Internal Medicine HomeNew OnlineCurrent IssueFor Authors Podcast Publications JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry (1919-1959) JN Learning / CMESubscribeJobsInstitutions / LibrariansReprints & Permissions Terms of Use | Privacy Policy | Accessibility Statement 2023 American Medical Association. All Rights Reserved Search All JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Forum Archive JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry Input Search Term Sign In Individual Sign In Sign inCreate an Account Access through your institution Sign In Purchase Options: Buy this article Rent this article Subscribe to the JAMA Internal Medicine journal