tbuckley/cabot-search huggingface dataset:
Effect of Interferon Administration on Pulmonary Osteogenic Sarcomas in an Experimental Murine Model&lt;xref ref-type="fn" rid="FN2"&gt;2&lt;/xref&gt;&lt;xref ref-type="fn" rid="FN3"&gt;3&lt;/xref&gt;
Authors: L A Glasgow, E R Kern
Journal: JNCI Journal of the National Cancer Institute (1981)

Journal Article Effect of Interferon Administration on Pulmonary Osteogenic Sarcomas in an Experimental Murine Model Get access Lowell A. Glasgow, Lowell A. Glasgow Search for other works by this author on: Oxford Academic PubMed Google Scholar Earl R. Kern Earl R. Kern Search for other works by this author on: Oxford Academic PubMed Google Scholar JNCI: Journal of the National Cancer Institute, Volume 67, Issue 1, July 1981, Pages 207–212, https://doi.org/10.1093/jnci/67.1.207 Published: 01 July 1981 Article history Received: 27 October 1980 Accepted: 29 January 1981 Published: 01 July 1981
Tofacitinib, an oral Janus kinase inhibitor, for the treatment of chronic plaque psoriasis: Long-term efficacy and safety results from 2 randomized phase-III studies and 1 open-label long-term extension study
Authors: Kim A. Papp, James G. Krueger, Steven R. Feldman, Richard G. Langley, Diamant Thaci, Hideshi Torii, Stephen Tyring, Robert Wolk, Annie Gardner, Charles Mebus, Huaming Tan, Yingchun Luo, Pankaj Gupta, Lotus Mallbris, Svitlana Tatulych
Journal: Journal of the American Academy of Dermatology (2016)

BackgroundTofacitinib is an oral Janus kinase inhibitor being investigated for psoriasis.ObjectivesWe sought to report longer-term tofacitinib efficacy and safety in patients with moderate to severe psoriasis.MethodsData from 2 identical phase-III studies, Oral-treatment Psoriasis Trial Pivotal 1 and 2, were pooled with data from these patients in an ongoing open-label long-term extension study. Patients (n = 1861) were randomized 2:2:1 to tofacitinib 5 mg, 10 mg, or placebo twice daily (BID). At week 16, placebo patients were rerandomized to tofacitinib. Pivotal study participants could enroll into the long-term extension where they received tofacitinib at 10 mg BID for 3 months, after which dosing could be 5 or 10 mg BID.ResultsAt week 28, the proportions of patients randomized to tofacitinib 5 and 10 mg BID achieving 75% or greater reduction in Psoriasis Area and Severity Index score from baseline were 55.6% and 68.8%, and achieving Physician Global Assessment of clear or almost clear were 54.7% and 65.9%. Efficacy was maintained in most patients through 24 months. Serious adverse events and discontinuations because of adverse events were reported in less than 11% of patients over 33 months of tofacitinib exposure.LimitationsThere was no dose comparison beyond week 52.ConclusionsOral tofacitinib demonstrated sustained efficacy in patients with psoriasis through 2 years, with 10 mg BID providing greater efficacy than 5 mg BID. No unexpected safety findings were observed.
Treating hypertension in patients with medical comorbidities
Authors: Lucinda Kennard, Kevin M O’Shaughnessy
Journal: BMJ (2016)

#### What you need to know

Hypertension affects more than one in four adults in the UK1 and prevalence is rising as the population ages. One British study found that around two in every three patients with hypertension has a comorbidity.2 Hypertension is a public health priority but may not be the individual patient’s priority. This mismatch may help to explain why in one study a quarter of all hypertensive patients did not fill out their first prescription,3 and in another, patients did not take their prescribed medication 50% of the time.4

Advice offered here to rationalise prescribing in patients with hypertension and comorbidities is taken from several guidelines from the National Institute for Health and Care Excellence (NICE): CG127, CG182 (chronic kidney disease), CG108 (chronic heart failure), CG87 (type 2 diabetes), NG17 (type 1 diabetes), CG180 (atrial fibrillation).5 6 7 8 9 10 When collating evidence, patients with multiple comorbidities or extremes of age are poorly represented in these datasets. These same patients are likely to have a substantial tablet burden already, so the emphasis here has been to suggest drugs that are most likely to benefit the patient’s blood pressure and comorbidity. By avoiding drugs with less clear benefits it is hoped drug side effects can be reduced and compliance increased.

With all hypertensive patients who would like to lower their blood pressure, discuss lifestyle modification including regular exercise, a low salt diet (<6 g/day), low alcohol and caffeine consumption, smoking cessation, and a healthy body weight. 

Fig 1 …
Preclinical activity of MM-111, a bispecific ErbB2/ErbB3 antibody in previously treated ErbB2-positive gastric and gastroesophageal junction cancer.
Authors: Johanna Lahdenranta, Violette Paragas, Arthur J. Kudla, Ryan Overland, Victor M. Moyo, Ulrik Nielsen, Charlotte McDonagh, Matthew Onsum
Journal: Journal of Clinical Oncology (2013)

48 Background: ErbB2 (HER2) overexpression has been reported in 7-34% of gastric cancers. ErbB3 (HER3) is the preferred dimerization partner of ErbB2, and ErbB2/ErbB3 heterodimer activation is implicated in the progression and metastasis of ErbB2+ tumors. Activation of ErbB3 signaling is a postulated resistance mechanism to current ErbB2-directed therapies and select chemotherapies. In line with this research, ErbB3 levels are associated with poor prognosis in gastric cancers. MM-111 is a bi-specific antibody that docks to ErbB2 and inhibits ErbB3 signaling in cells that overexpress ErbB2. In this study, MM-111 was evaluated in ErbB2+ gastric cancer by testing the activity of MM-111 in ErbB2+ pre-clinical models of gastric cancer, and by assessing the prevalence of potentially predictive biomarkers in a panel of archived gastric and gastroesophageal junction (GEJ) tumors. Methods: MM-111 was tested in ErbB2+ gastric cancer xenografts that were either untreated or after tumors ceased to respond to trastuzumab/5-FU. Xenografts were analyzed at multiple time points for the expression of ErbB-receptor family members and their downstream signaling by Luminex -assays. Preclinical data indicate that ErbB2, ErbB3, and heregulin are predictive biomarkers for MM-111. In order to determine the prevalence of our potentially predictive biomarkers in gastric and GEJ cancers, we obtained commercially archived tumor tissue and assayed the tissue for ErbB2 and ErbB3 expression levels using quantitative IHC, and measured heregulin transcript levels by RT-PCR. Results: MM-111 synergizes with various treatment regimens in the 2 nd line treatment setting in ErbB2+ gastric cancer xenografts. In our models, the combination of MM-111, trastuzumab, and paclitaxel is particularly effective after tumors progressed on trastuzumab/5-FU. MM-111 inhibits the activity of the ErbB –signaling axis in these models. In addition, 23% of GEJ tumor samples and 20% of gastric samples were positive for potentially predictive biomarkers. Conclusions: ErbB2+xenograft tumors that stop responding to trastuzumab-based therapies benefit from MM-111–based regimens.
iTARGET: A phase II trial to assess the response to gefitinib in epidermal growth factor receptor (<i>EGFR</i>)-mutated non-small cell lung cancer (NSCLC) tumors
Authors: L. V. Sequist, R. G. Martins, D. Spigel, S. M. Grunberg, P. A. Jänne, D. McCollum, A. Spira, T. Evans, B. E. Johnson, T. J. Lynch
Journal: Journal of Clinical Oncology (2007)

7504 Background: Somatic EGFR mutations correlate with increased response and survival in NSCLC patients (pts) treated with gefitinib. We conducted the 1st prospective US trial of 1st-line gefitinib in pts with advanced NSCLC harboring EGFR mutations. Methods: Chemotherapy-naïve pts with stage IIIB with effusion or IV NSCLC, measurable disease, and = 1 characteristic associated with mutations (female (F), adenocarcinoma (AC), never-smoking (NS), East Asian (EA)) underwent direct DNA sequencing of tumor tissue EGFR exons 18–24. Mutation-positive pts received gefitinib (250 mg/d) until progression or unacceptable toxicity. The primary outcome was response rate (RR) by RECIST criteria. Results: We sequenced 98 pts and detected EGFR mutations in 34 (35%); 3 were not assessable. Observed mutations were 18 (53%) exon 19 deletions (del), 9 (26%) L858R, 3 (9%) exon 20 insertions (ins), 2 T790M/L858R, 1 G719A, and 1 L861Q. Characteristics of the 98 screened pts were 69 F, 89 AC, 37 NS, and 5 EA; those of the 34 mutation pts were 20 (59%) F, 31 (91%) AC, 19 (56%) NS and 2 (6%) EA. The best predictor of EGFR mutation was NS. Of the 34 mutation pts, 31 (91%) received gefinitib. Reasons for non-treatment were pt preference (1 exon 19 del) and mutation associated with gefitinib-resistance (1 T790M/L858R, 1 exon 20 ins). Adverse events were mainly grade 1–2 rash and diarrhea; 1 case of grade 4 interstitial lung disease occurred after 2 weeks of therapy. The RR was 58% (95% confidence interval 39–75) and was 78% in L858R pts and 65% in del 19 pts. There were no responses among the G719A, L861Q, T790M/L858R and exon 20 ins pts treated. 12 pts have progressed, 18 remain on therapy. The median progression-free survival (PFS) is currently 11.8 mo and does not differ by mutation type, though follow-up is short (median 6.8 mo, range 1–24). 27 pts are still alive. Of the 31 pts treated, 22 (71%) had high EGFR gene copy number (amplification (3) or high polysomy (19)); RR and PFS did not vary by copy number. Conclusions: 1st-line gefitinib therapy in EGFR mutation-positive NSCLC pts is feasible in a multi-institutional study, well tolerated, and yields a substantial RR and PFS. This strategy should be compared to standard chemotherapy in a genotype-directed randomized trial. No significant financial relationships to disclose.
Impact of neutropenia on chemotherapy administration in elderly patients with advanced non-small cell lung cancer (NSCLC)
Authors: K. B. Knopf, J. Lipscomb, T. W. Gillespie, M. E. Stokes, C. E. Muehlenbein, D. Faries, M. D. Marciniak, S. Motabar, D. P. Buesching
Journal: Journal of Clinical Oncology (2008)

9624 Background: Neutropenia is an important toxicity that can lead to chemotherapy dose reductions. The purpose of this study was to quantify the impact of neutropenia on first- and second-line dose reductions in NSCLC. Methods: A retrospective analysis of electronic medical records obtained from medical oncology practices in 14 states was conducted. Patients aged 65 years or older with a record indicating receipt of chemotherapy during 1997 through June 2007 were selected. Neutropenia was identified as a neutrophil count less than 1.0 × 109/L. Chemotherapy dose reductions were defined as dose density (mg/m2/week) decreases of at least 10% from the average of preceding administrations. Characteristics associated with neutropenia and dose reductions were assessed using multivariate logistic regression models. Results: Among elderly patients treated first-line for advanced NSCLC, 3,263 were identified who met inclusion criteria. Approximately 20% (N=684) developed neutropenia while on first-line chemotherapy. Forty percent (N=1,295) went on to receive second-line chemotherapy, among whom, 19.4% (N=251) developed neutropenia during second-line treatment. Multivariate logistic regression analyses showed that prophylactic receipt of pegfilgrastim or filgrastim (growth factors) was associated with a lower risk of neutropenia during first-line (OR 0.62; 95% CI 0.43 - 0.88) and second-line chemotherapy (OR 0.36; 95% CI 0.18 - 0.74). Factors associated with dose reductions during first-line treatment included age ≥ 75 compared to < 75 (OR 1.19; 95% CI 1.004 - 1.42) and neutropenia during first-line (OR 1.60; 95% CI 1.29 - 1.98) versus no neutropenia. Conclusions: Patients at least 75 yrs old and patients developing neutropenia during first-line chemotherapy were more likely to undergo a dose reduction compared to younger patients and patients without neutropenia. Patients receiving prophylactic growth factors were less likely to develop neutropenia. These findings suggest that the dose limiting effects of neutropenia may be mitigated with primary prevention. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration Eli Lilly Eli Lilly, United BioSource Eli Lilly
Abstract 11115: Proprotein Convertase Subtilisin/Kexin Type 9 Regulates Migration of Mononuclear Cells
Authors: Isabell A Just, Heike Meyborg, Sandra Molnar, Daniel Urban, Ulrich Kintscher, Eckart Fleck, Philipp Stawowy
Journal: Circulation (2014)

Introduction:  Mononuclear cell (MNC) migration is a key element in atherogenesis. LDL-C has been found to facilitate MNC migration via LDL-R related upreguation of CCR2. PCSK9 regulates serum LDL-C via degradation of hepatic LDL-R′s. Recently, PCSK9-expression, lacking in MNCs, has been demonstrated in VSMCs of the vessel wall. Thus, the present study was done to explore the regulation of PCSK9 in VSMCs by inflammation and the impact of VSMC-derived PCSK9 on MNC function.   Methods and Results:  PCSK9 mRNA and protein levels were upregulated by the TLR4-ligand lipopolysaccharide (LPS; 100 ng/ml), whereas TGF-β or angiotensin II had no effect. LPS increased PCSK9 mRNA and protein Levels time- and concentration dependently. This was selectively inhibited by TLR4 Blockade with CLI-059 and further downstream with the JNK-inhibitor SP600125, whereas inhibitors of ERK1/2, p38 or PI3-kinase pathways had no effect. ELISA-based analyses demonstrated that LPS significantly increased PCSK9 releases from VSMCs, which was further augmented by atorvastatin (10 μM). Incubation of human monocytic THP-1 cells in conditioned media from LPS-stimulated VSMCs resulted in a significant reduction of LDL-R levels in MNCs, comparable to the effects of recombinant PCSK9. In contrast, stimulation of MNCs with LPS alone did not affect MNC LDL-R levels. However, LDL (100 μg/mL) stimulation of MNCs increased their CCR2 expression, which augmented MNC migration towards MCP-1. This LDL-dependent MNC migration was inhibited by supernatants from LPS-stimulated VSMCs, comparable to the effects of recombinant PCSK9 or a functional LDL-R blocking antibody.   Conclusion:  PCSK9 is upregulated in VSMCs by TLR4/JNK signaling, a pathway important in inflammation and metabolism. VSMC-derived PCSK9 lessens MNC LDL-R expression, effecting LDL-C/LDL-R-mediated CCR2-expression on MNCs, crucial to MNC motility. In conclusion our data suggests PCSK9 as a key regulator in VSMCs / MNC interaction fundamental to CVD genesis.
Secondary breast cancer in patients treated for Hodgkin lymphoma: Adherence to screening recommendations in a high-risk population
Authors: A. Fontaine, K. A. Gelmon, J. M. Connors, K. J. Savage
Journal: Journal of Clinical Oncology (2008)

1540 Background: The survival of patients (pts) treated for Hodgkin's lymphoma (HL) has improved dramatically in the past few decades, however, secondary complications, including breast cancer (SBC), remain a serious late effect of treatment. Screening mammography (SM) has been recommended starting 10 years after completion of treatment of HL. It became widely available in British Columbia in 1988. Methods: Using the BCCA Lymphoid Cancer Database and the BCCA Breast Cancer Outcomes and Surveillance Database, we retrospectively reviewed all females who were treated for HL and subsequently developed breast cancer. Results: 62 female pts treated for HL between April 1963 and March 2002 were found to subsequently have developed SBC. The median age at diagnosis of HL was 24 y (12-86). 53 pts received radiotherapy (RT) as part of HL treatment, mainly mantle field (45, 73%). 35 pts received multiagent chemotherapy (9 alone and 26 combined with RT). SBC was diagnosed after a median latency from the diagnosis of HL of 20y (1.5–37). Median age at diagnosis of SBC was 49y (29–90). Most pts had their SBC discovered by self-detection or physician exam (n=36, 58%), 19 (31%) were diagnosed by SM and detection method was unknown for 7 patients. Among SBC diagnosed after 1988, (n=56), only 2/14 patients < 40 y had undergone SM compared to 26/42 diagnosed > 40 y. Overall, 6 women had a false-negative SM. SBC stage was (n) in situ disease (8), stage I (22), stage II (16), stage III (8), stage IV (5) and unknown (3). Most breast tumours were ductal carcinomas (48) (mixed histology 7, lobular 3). The majority of tumours were ER/PR-positive (n=30, 48%); 13 were negative and 19 unknown. Her-2-Neu expression was reported for 25 cases (20 negative, 5 positive). Conclusions: SBC constitutes a serious threat for female with a history of HL, particularly those treated with RT. Despite provincial guidelines in place, only a small proportion of women are being diagnosed following SM. Both pts and physicians must become more aware of screening recommendations and better means of encouraging appropriate screening must be found. No significant financial relationships to disclose.
A phase II study of temozolomide plus pegylated interferon alfa-2b for recurrent anaplastic glioma and glioblastoma multiforme
Authors: M. D. Groves, V. Puduvalli, M. R. Gilbert, C. A. Conrad, S. Hsu, H. Colman, K. Hess, V. A. Levin, W. K. A. Yung
Journal: Journal of Clinical Oncology (2005)

1519 Background: Based on prior studies suggesting promise of interferon alfa-2b and temozolomide (TMZ) in relapsed malignant glioma patients, we are testing this combination with a long acting (pegylated) form of interferon alfa-2b (PIFN) prolonging drug exposure and attempting to increase anti-tumor activity. Methods: We are conducting a prospective phase II trial of TMZ plus PIFN in adult patients with recurrent anaplastic glioma (AG) and glioblastoma multiforme (GBM), after surgery and radiotherapy (and chemotherapy in some cases), with adequate organ function and KPS ≥60. TMZ is administered at 150–200 mg/m2/day on days 1–5 of each 28-day cycle, and PIFN is administered subcutaneously at 0.5 microgram/kg every week. Two 28-day cycles equals one course. Patients are re-evaluated with neurological examinations and neuro-imaging every 56 days. The study is powered to detect an improvement of the historic 6-month progression-free survival (PFS) from 15% to 30% for GBM patients and from 20% to 40% for AG patients.Results: Thirty-five patients have enrolled, 9 with recurrent AG and 26 with recurrent GBM, 15 women, 20 men, median age is 55 years (range 20–67), median KPS is 90 (range 70–100). Grade 3 or 4 toxicity occurred in 29 patients, 10 patients required dose reduction, 2 of TMZ, 8 of both drugs. Common grade 3 or 4 toxicities included leukopenia or thrombocytopenia in 15 patients. Best responses were no change in 23/34 (68%). Kaplan-Meier estimates revealed 38% of GBM patients and 44% of AG patients alive and free from progression at 6 months after enrollment. Conclusions: Preliminary results of TMZ combined with PIFN in recurrent AG and GBM, despite a lack of any objective radiologic responses, produced a 6 month PFS in both subgroups that surpasses the target 6 month PFS. This improved outcome appears to come at a price of increased toxicity. This combination may warrant further investigation in a randomized trial or with other anti-neoplastic agents. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Schering-Plough
A multi-targeted approach to suppress tumor-promoting inflammation
Authors: Abbas K. Samadi, Alan Bilsland, Alexandros G. Georgakilas, Amedeo Amedei, Amr Amin, Anupam Bishayee, Asfar S. Azmi, Bal L. Lokeshwar, Brendan Grue, Carolina Panis, Chandra S. Boosani, Deepak Poudyal, Diana M. Stafforini, Dipita Bhakta, Elena Niccolai, Gunjan Guha, H.P. Vasantha Rupasinghe, Hiromasa Fujii, Kanya Honoki, Kapil Mehta, Katia Aquilano, Leroy Lowe, Lorne J. Hofseth, Luigi Ricciardiello, Maria Rosa Ciriolo, Neetu Singh, Richard L. Whelan, Rupesh Chaturvedi, S. Salman Ashraf, H.M.C. Shantha Kumara, Somaira Nowsheen, Sulma I. Mohammed, W. Nicol Keith, William G. Helferich, Xujuan Yang
Journal: Seminars in Cancer Biology (2015)

Cancers harbor significant genetic heterogeneity and patterns of relapse following many therapies are due to evolved resistance to treatment. While efforts have been made to combine targeted therapies, significant levels of toxicity have stymied efforts to effectively treat cancer with multi-drug combinations using currently approved therapeutics. We discuss the relationship between tumor-promoting inflammation and cancer as part of a larger effort to develop a broad-spectrum therapeutic approach aimed at a wide range of targets to address this heterogeneity. Specifically, macrophage migration inhibitory factor, cyclooxygenase-2, transcription factor nuclear factor-κB, tumor necrosis factor alpha, inducible nitric oxide synthase, protein kinase B, and CXC chemokines are reviewed as important antiinflammatory targets while curcumin, resveratrol, epigallocatechin gallate, genistein, lycopene, and anthocyanins are reviewed as low-cost, low toxicity means by which these targets might all be reached simultaneously. Future translational work will need to assess the resulting synergies of rationally designed antiinflammatory mixtures (employing low-toxicity constituents), and then combine this with similar approaches targeting the most important pathways across the range of cancer hallmark phenotypes.
Abstract 777: Caveolin-1 Regulates NADPH Oxidase Subcellular Location And Activity In Endothelial Cells.
Authors: Baohua Yang, Victor J Rizzo
Journal: Circulation (2007)

Background: The biological setting or location where reactive oxygen species (ROS) are produced is a new concept which may provide a mechanistic explanation for redox signaling specificity. In this regard, we recently reported that NADPH oxidase, a major superoxide producing enzyme system, is localized and functional in endothelial cell caveolae. Here, we investigate the role of caveolin-1, the main structural protein of caveolae, in the organization and regulation of NADPH oxidase activity and ROS mediated responses to cytokine challenge. Methods and Results: Superoxide production was measured by DHE assay in endothelial cells derived from wild type (wt) and caveolin-1 knockout (Cav−/ −) mouse lungs (MLEC). TNFα failed to induced superoxide production in Cav−/ − endothelial cell cultures (MOI = 0). However, infection of knockout cells with full-length caveolin-1 containing Adenovirus at MOI of 10 and 50 progressively restored TNFα effect on superoxide production with MOI 50 nearly reaching those observed in wt cells. The distribution of NADPH oxidase within the plasma membrane showed localization to membrane rafts fractions in wt cells which shifted to the non-raft membrane fractions in Cav-1−/ − MLEC. Re-expression of caveolin-1 (MOI 50) restored raft targeting of NADPH oxidase and both gp91 and p22phox co-precipitated with newly expressed caveolin-1 immunoprecipitated from raft fractions. To evaluate the cellular consequences of a potential redox signaling relay involving caveolin-1, we examined an NADPH oxidase dependent pathway involving activation of JNK1/2 MAP kinases and downstream upregulation of ICAM. We found that phosphorylation of JNK1/2 observed in wt MLEC in response to TNFα was significantly attenuated in Cav−/ − MLEC. In addition, TNFα did not induce upregulation of ICAM expression in caveolin-1 knockout MLEC or wt cells pretreated with DPI. Conclusions: Collectively, these results indicate that caveolin-1 is a necessary component of the molecular machinery for proper subcellular positioning required for cytokine activation of NADPH oxidase and superoxide production in endothelial cells. Thus, caveolin-1 may constitute a potential therapeutic target for altering ROS associated with cardiovascular pathology.