tbuckley/cabot-search huggingface dataset:
P33 Rituximab as rescue therapy in advanced progressive systemic sclerosis associated interstitial lung disease
Authors: M Kokosi, P Saunders, K Karagiannis, F Chua, TM Maher, EA Renzoni, AU Wells
Journal: Thorax (2015)

<h3>Introduction</h3> Severe interstitial lung disease associated with systemic sclerosis (SSc-ILD) often has an inexorably progressive course. Prevention or retardation of disease progression (as seen in both SLS and the FAST trials) is the only realistic treatment goal in most cases. Rituximab is a B- lymphocyte depleting monoclonal antibody which has proven efficacy in a spectrum of treatment-refractory interstitial lung diseases. Data on the impact of rituximab therapy on SSc-ILD outcomes are limited. <h3>Methods</h3> 18 patients with severe progressive SSc-ILD, despite conventional immunosuppression, were studied retrospectively. Serial change in FVC and DLco was quantified as percentage relative change from baseline, Pulmonary function trends pre (3–17 months) and post (3–11 months) Rituximab therapy were compared using paired t-testing. <h3>Results</h3> 18 patients (four male), with a median age 57.5 (±15.9) received treatment with rituximab between 2012 and 2014. The median follow-up period was 7.96 (range 3.1–11.2) months. One patient died from heart failure. Rituximab was well tolerated. At the time of rituximab treatment, patients had severe pulmonary function impairment (median FVC 50.5%, range 36–84%; median DLco 25%, range 14–41%). On paired testing, there was a reduction in serial FVC decline following Rituximab therapy (-10.1% ± 7.8% versus -1.5% ± 8.7%, p = 0.01) and a similar reduction in serial DLco decline (-15.6% ± 16.8% vs. 1.0% ± 27.2%, p = 0.05). <h3>Conclusion</h3> The addition of Rituximab was associated with a significant reduction in serial pulmonary function decline in patients with advanced progressive SSc-ILD, not controlled by intense conventional immunomodulation. These findings provide further support for the use of Rituximab as rescue therapy in severe SSc-ILD.
Effect of Spectinomycin Use on the Prevalence of Spectinomycin-Resistant and of Penicillinase-Producing<i>Neisseria Gonorrhoeae</i>
Authors: John W. Boslego, Edmund C. Tramont, Ernest T. Takafuji, Benedict M. Diniega, Benjamin S. Mitchell, James W. Small, Waheed N. Khan, Daniel C. Stein
Journal: New England Journal of Medicine (1987)

Because of the high prevalence of penicillinase-producing Neisseria gonorrhoeae in the Republic of Korea, spectinomycin has been used there in the primary treatment of gonococcal infections in U.S. military personnel since 1981, but there have been increasingly frequent reports of treatment failures with spectinomycin. We conducted a clinical study to determine the efficacy of spectinomycin treatment in 124 U.S. servicemen in the Republic of Korea who had urethral gonococcal infections. Ninety-seven patients were treated with spectinomycin alone and evaluated in a follow-up visit. In eight patients (8.2 percent), this treatment was unsuccessful. Antibiotic-sensitivity testing on isolates from seven of the patients with treatment failure demonstrated that six isolates were highly resistant to spectinomycin (minimal inhibitory concentration, greater than or equal to 100 micrograms per milliliter). None of the spectinomycin-resistant strains had become resistant to penicillin, either through the production of penicillinase or through a chromosomal mutation. Although the mechanism of spectinomycin resistance appears to be a chromosomal mutation, these isolates were generally sensitive to other antibiotics. The prevalence of resistance to spectinomycin resulted in the substitution of ceftriaxone for the primary treatment of gonorrhea acquired by U.S. military personnel in the Republic of Korea. We believe that the rapid emergence of spectinomycin resistance in this population mandates a cautious approach to widescale use of the drug and indicates a need to broaden current surveillance programs.
In Vitro Immune Responsiveness to Vaccinia Virus and HLA
Authors: René R. P. de Vries, Hans G. Kreeftenberg, Henk G. Loggen, Jon J. van Rood
Journal: New England Journal of Medicine (1977)

Because several lines of evidence suggest that HLA products might have an important function in the immune response to infectious agents, we studied the possible relation between immune response to vaccinia virus and HLA phenotype in 79 soldiers who received a primary vaccination. A low in vitro response to vaccinia virus was associated with HLA-Cw3 both in 49 subjects tested three to four weeks after vaccination (P<0.001) and in the remaining 30 subjects tested five to 11 weeks after vaccination (P = 0.035). Responses to unrelated antigens and phytohemagglutinin of lymphocytes tested before, three to four weeks and five to 11 weeks after vaccination indicated that this association was specific for vaccinia virus and suggested that differences in immune response to vaccinia were reflected in temporarily altered immune responsiveness to unrelated antigens. Our results indicate that HLA-Cw3 or an HLA product associated with Cw3 is involved in the cellular immune response to vaccinia virus. (N Engl J Med 297:692–696, 1977)
Fatal Agranulocytosis Following Therapy with “Presidon” (3,3-Diethyl-2,4-Dioxotetrahydropyridine), a New Sedative Hypnotic Agent
Authors: Albert H. Covner, Seymour L. Halpern
Journal: New England Journal of Medicine (1950)

AMONG the nonbarbiturate sedative drugs that have recently been introduced has been 3,3-diethyl-2,4-dioxotetrahydropyridine (pyrithyldione), which has been marketed under the trade name of Presidon. The drug was advertised as a sedative hypnotic predictable in its effect, rapid in onset, with negligible side effects, little tendency to habit formation, slight properties of tolerance and completely nontoxic and safe.A case of fatal agranulocytosis is presented below, since it is believed that Presidon was the etiologic agent responsible for the patient's fatal illness. It indicates that this sedative hypnotic may not be the safe drug it is believed to be. Since most . . .
Evaluation of the dual tyrosine kinase inhibitor lapatinib in combination with 5-fluorouracil and SN-38 in colon and gastric cell line models
Authors: M. J. Labonte, P. M. Wilson, W. Fazzone, H. J. Lenz, R. D. Ladner
Journal: Journal of Clinical Oncology (2008)

14643 Background: Inhibition of members of the HER-family remains an important therapeutic strategy in multiple malignancies. Lapatinib (Tykerb) is a dual EGFR HER-2-targeted tyrosine kinase inhibitor currently approved in combination with the oral 5-fluorouracil (5-FU) pro-drug capecitabine for the treatment of breast cancer patients who have previously failed multiple therapies. To better understand the mechanistic basis for lapatinib combination therapy, this study investigated the interaction between Lapatinib and 5-FU and irinotecan in two colon (HT-29 and LoVo) and two gastric (AGS and MKN-28) cell line models with varying EGFR and HER-2 levels. Methods: EGFR and HER-2 expression levels were determined by Western blotting. Response of colon and gastric cell lines to treatment with Lapatinib, 5-FU and SN-38 (irinotecan active metabolite) was evaluated by MTT growth inhibition and cell survival assays. Drug combinations were evaluated by combination indices using the methods of Chou-Talalay. Flow cytometric analysis was employed to analyze cell cycle effects and induction of apoptosis in selected drug combinations. DNA damage was quantified by detection of H2A.X phosphorylation in response to DNA double strand breaks. Results: Lapatinib in combination with either 5-FU or SN-38 resulted in synergistic growth inhibition in all gastric and colon cell line models tested with varying EGFR and HER-2 status. Furthermore, the triple combination of Lapatinib, SN-38 and 5-FU resulted in highly synergistic growth inhibition. In addition, Lapatinib in combination with SN-38 demonstrated highly synergistic suppression of clonogenic cell survival. Flow cytometric analysis demonstrated that the addition of Lapatinib to SN-38 dramatically enhanced cell cycle arrest at the G2/M checkpoint, rapidly activated caspase-8, and potently induced apoptotic cell death. Analysis of H2A.X indicated that Lapatinib enhanced the generation of SN-38-induced DNA double-strand breaks. Conclusions: These data provide compelling preclinical rationale supporting the inclusion of Lapatinib in gastrointestinal chemotherapeutic regimens containing irinotecan and 5-FU. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration Pfizer Oncology GlaxoSmithKline, Pfizer Oncology
PWE-300 Perineal wound complications in the era of extralevator abdominoperineal excision of the rectum (elape)
Authors: C Mann, E Bown, D Couch, S Bhandari, K Boyle
Journal: Gut (2015)

<h3>Introduction</h3> ELAPE is associated with improved oncological outcome compared to traditional abdominoperineal excision of the rectum (APER) and has become the standard surgical technique for low rectal cancers in many centres. It is however associated with large perineal defect, encouraging some surgeons to routinely reconstruct the pelvic floor using a mesh, and may be associated with high rates of wound morbidity. The aim of study was to review the rate of perineal wound complications following ELAPE in our centre. <h3>Method</h3> All patients undergoing ELAPE for adenocarcinoma of the rectum at Leicester Royal Infirmary between January 2010 and September 2014 were identified from the prospectively maintained colorectal MDT database. Patient notes and computer records were reviewed to obtain data on the perineal closure technique and perineal wound complications, specifically wound breakdown and symptomatic perineal herniation. <h3>Results</h3> 71 patients were included in the study - 38 were male, with a median age of 71 (range 46–88) years. Eighty-nine percent underwent pre-operative long-course chemoradiotherapy. R<sub>0</sub>resection was achieved in 96%. Sixty-eight patients underwent primary perineal wound closure including omentoplasty where possible; biological mesh was used in 1 patient and 2 underwent myocutaneous flap reconstruction. Thirty-nine percent of patients developed a perineal wound complication, with 13 percent developing a deep infection associated with wound breakdown–of these 69% required surgical intervention/Vac therapy. Three patients developed a late perineal sinuses. A symptomatic perineal hernia developed in four patients (5.6%), three of whom opted for conservative management; one is currently awaiting surgical repair. <h3>Conclusion</h3> This is a large single centre series of ELAPE with good R<sub>0</sub>resection rates. ELAPE remains associated with high rates of perineal wound morbidity. We feel that the symptomatic perineal hernia rate is not high enough to justify routine use of biological mesh, and therefore a pragmatic approach to perineal reconstruction should be taken on individual patient basis, depending on tumour size and patient anatomy. <h3>Disclosure of interest</h3> None Declared.
Prothrombin and Factor V Mutations in Women with a History of Thrombosis during Pregnancy and the Puerperium
Authors: Andrea Gerhardt, Rüdiger Eberhard Scharf, Matthias Wilhelm Beckmann, Sabine Struve, Hans Georg Bender, Michael Pillny, Wilhelm Sandmann, Rainer Bernd Zotz
Journal: New England Journal of Medicine (2000)

Venous thromboembolism is a leading cause of morbidity and mortality during pregnancy and the puerperium. However, the role of mutations in the prothrombin and factor V genes and other thrombophilic abnormalities as risk factors for thromboembolism in women during pregnancy and the puerperium is not known.
Study of Left Ventricular Geometry and Function by B-Scan Ultrasonography in Patients with and without Asynergy
Authors: Louis E. Teichholz, Michael V. Cohen, Edmund H. Sonnenblick, Richard Gorlin
Journal: New England Journal of Medicine (1974)

To assess the usefulness of B-scan ultrasonography in determining left ventricular geometry and function, 25 patients with various cardiac disorders were studied with B-scan imaging within 24 hours of performance of biplane cine angiography of the left ventricle. In 14 patients asynergy present on the left anterior oblique ventriculogram was also detected on the B-scan image. A good correlation was found between the area ejection fractions as determined from the B-scan and the ventriculographic silhouettes (r = 0.92). A good correlation was also found between the B-scan area ejection fraction and the biplane volume ejection fraction (r = 0.87), even in patients with left ventricular asynergy, in whom the quantification of left ventricular geometry and function by standard time-motion echocardiography may be inaccurate. Thus, B-scan ultrasonography appears to be a safe, noninvasive, easily repeated technic for the study of left ventricular geometry, ejection and segmental motion in patients with various forms of heart disease. (N Engl J Med 291:1220–1226, 1974)
Abstract 2529: Debio 1143 synergizes with taxanes, topoisomerase and bromodomain inhibitors to inhibit growth of lung adenocarcinoma
Authors: Casey G. Langdon, Norbert Wiedemann, Matthew A. Held, James T. Platt, Ramanaiah Mamillapalli, Pinar Iyidogan, Nicholas Theodosakis, Frederic Levy, Denis Robichon, Claudio Zanna, Gregoire Vuagniaux, Mel Sorensen, Shaomeng Wang, Marcus W. Bosenberg, David F. Stern
Journal: Cancer Research (2015)

Abstract Efficient induction of cell death is essential for efficacy of cancer therapies, and may be enhanced in combination therapies that promote apoptosis. Small molecule mimetics of the pro-apoptotic protein SMAC antagonize Inhibitor of Apoptosis Proteins (IAPs). Debio 1143 is a potent oral SMAC mimetic currently assessed in clinical trials in combination with chemo- and radiotherapy in different cancer indications. We have conducted a “one vs. many” drug combination screen in which Debio 1143 is combined pairwise with a panel of 128 candidate partner agents in order to identify drug combinations that inhibit growth of lung adenocarcinoma cells. Several synergistic Debio 1143 combinations were selected for further analysis. We confirmed that Debio 1143 synergistically inhibited growth in combination with taxanes paclitaxel and docetaxel, topoisomerase inhibitor SN-38, and the bromodomain inhibitor JQ1. The combination of Debio 1143 with any of these agents further inhibited clonogenic colony formation and induced apoptosis more than either agent alone. In two Debio 1143-sensitive cell lines Debio 1143 also induced formation of the cell-death inducing complex - the ripoptosome. Interestingly, while Debio 1143 broadly reduced protein levels of cIAP1 across cell lines, specifically the combination with JQ1 also reduced cIAP2 and XIAP levels and inhibited the canonical NF-κB pathway while inducing the non-canonical NF-κB pathway. Overall, these data support utility of several combinations of Debio 1143 with other agents, especially bromodomain inhibitors, in lung adenocarcinoma and other cancers. Specifically, these findings indicate that the synergy between JQ1 and Debio 1143 may derive from JQ1 contributing on different levels to key mechanisms relevant for SMAC mimetic antitumor activity. Citation Format: Casey G. Langdon, Norbert Wiedemann, Matthew A. Held, James T. Platt, Ramanaiah Mamillapalli, Pinar Iyidogan, Nicholas Theodosakis, Frederic Levy, Denis Robichon, Claudio Zanna, Gregoire Vuagniaux, Mel Sorensen, Shaomeng Wang, Marcus W. Bosenberg, David F. Stern. Debio 1143 synergizes with taxanes, topoisomerase and bromodomain inhibitors to inhibit growth of lung adenocarcinoma. [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 2529. doi:10.1158/1538-7445.AM2015-2529
Identification of a basal-like subtype and comparative effect of epirubicin-based chemotherapy and sequential epirubicin followed by docetaxel chemotherapy in the PACS 01 breast cancer trial: 33 markers studied on tissue-microarrays (TMA)
Authors: J. Jacquemier, F. Penault-Llorca, H. Mnif, E. Charafe-Jauffret, S. Marque, A. Martin, J. Genève, H. Roché
Journal: Journal of Clinical Oncology (2006)

509 Background: Immunohistochemical profiling studies with TMA classified breast cancer by luminal, normal breast like, HER-2 overexpressing, and basal-like subtypes. The aim of this study was to evaluate the impact of these subclasses in terms of therapeutic benefit for patients (pts) with node positive operable breast cancer included in the phase III trial PACS01. Methods: Among the 1999 pts randomized, 1100 paraffin blocs were collected for TMA. Pts were treated with either arm A: 6 cycles of FEC100 (546 pts) or arm B: docetaxel 100 mg/m 2 replaced FEC100 for the last 3 cycles (554 pts). The median follow up was 5 years. The 33 analysed markers explored different pathways: cellular differentiation (CK5/6,8/18,14, P-Cadherin, E-cadherin, α-catenin, β-catenin, AF6, MUC1, Cav1, moesin, Cd10, CD44), proliferation/apoptosis (AuroraA, Tacc2/3, Ki67, CyclinD1, Bcl2, p21, p27), ER related (ER, PR, Gata3), and oncogene/ antioncogene (P53, HER2, EGFR1, Pten, Cmet, Fhit, FGFR, Angiogenin, topoisomeraseIIα). All antibodies were evaluated in quick score. Results: In terms of metastases free survival (MFS) 16 markers harboured a statistical significant value under 20%. The hierarchical clustering for 80% of complete data, identify a cluster of pts (n=531) characterized by the positive expression of EGFR1, Moesin, Pcadherin, and p53, considered as basal-like subtype (BLST). This cluster presented a pejorative predictive value both in Log-rank test (LR) (p=0.002) and in Cox multivariate analysis (HR=0.65; p=0.009), confirmed in overall survival (OS) (LR p&lt;0.0001; cox HR=0.46, p&lt;0.001). BLST pts had a significantly better MFS (LR p=0.05) in the arm B, confirmed in OS (LR p=0.005), as for a more theoretical basal signature and ER negativity (LR MFS p=0.0033, OS p=0.0052; cox MFS HR=0.71 p=0.04, OS HR=0.51 p=0.003). For a second cluster considered as luminal subtype (ER positive and BLST parameters negatives) no difference was observed whatever the arm. Conclusions: The basal-like profile identified in this study is significantly associated to a worst prognostic, but also to a better response to sequential FEC/docetaxel chemotherapy. [Table: see text]
Phase I study of SB939 three times weekly for 3 weeks every 4 weeks in patients with advanced solid malignancies
Authors: W. Yong, B. Goh, H. Toh, R. Soo, V. Diermayr, A. Goh, K. Ethirajulu, S. Lee, E. Seah, J. Zhu
Journal: Journal of Clinical Oncology (2009)

2560 Background: SB939 is a novel orally bioavailable inhibitor of class 1 and 2 histone deacetylases. We conducted a phase I study to assess the safety, maximum tolerated dose (MTD), pharmacokinetics, pharmacodynamics and preliminary efficacy of SB939 in patients with advanced solid malignancies. Methods: SB939 was administered orally every other day 3 times a week for 3 consecutive weeks, in a 4-week cycle. Cohorts of patient were treated with escalating doses of SB939 starting from 10 mg. PK and PD (Acetylated Histone 3 in PBMCs) samples were collected in the first cycle. Results: 31 patients were enrolled at 10 mg (n=3), 20 mg (4), 40 mg (8), 60 mg (10) and 80 mg (6). The median number of treatment cycles received was 3.6. Fatigue, elevation of troponin T and QTc prolongation were the observed dose-limiting toxicities (DLT). At 80mg, one patient each (3/6) experienced a DLT of grade 3 fatigue, grade 3 asymptomatic elevation of troponin T and grade 3 QTc prolongation respectively. All DLTs were reversible and no treatment mortality was observed. Grade 1–2 fatigue occurred in 56% of patients occurring mainly at the 4 th week, and 37% of pts had G1–2 anorexia. Grade 3–4 thrombocytopenia was observed in 2 patients at 60 mg at cycles 1 and 6 of treatment. SB939 was rapidly absorbed reaching Tmax between 1–3 h after ingestion, and mean elimination half-life and oral clearance of SB939 were 7.2 + 0.6 hrs and 53 + 8.5 L/h respectively. C max and AUC (0-∞) were dose-proportionally increased at this dose range. There was no substantial accumulation of SB939 on day 15 following repeated dosing. Concentrations above IC50 of SB939 for HDAC I was reached at all doses. Acetylation of H3 was dose dependent and consistent at 60mg. Of the 13 patients evaluable for response, stable disease was seen in 1 patient with follicular thyroid carcinoma and 1 with hepatocellular carcinoma for 51 and 164 days respectively. Conclusions: SB939 has similar toxicity profiles as that of other HDAC inhibitors and a favorable PK/PD profile. The MTD of SB939 in this regimen was 80 mg and 60mg is the recommended dose, at which acetylation of H3 is consistently observed. Further phase 2 studies with SB939 in specific indications are being planned. No significant financial relationships to disclose.
CORRESPONDENCE
Authors: Tuan V. Nguyen, Giang N. Trinh
Journal: Journal of Clinical Oncology (2002)

Article Tools SPECIAL DEPARTMENTS Article Tools OPTIONS & TOOLS Export Citation Track Citation Add To Favorites Rights & Permissions COMPANION ARTICLES No companion articles ARTICLE CITATION DOI: 10.1200/JCO.2002.20.3.878 Journal of Clinical Oncology - published online before print September 21, 2016 PMID: 11821478 CORRESPONDENCE Clinical Evaluation of Once-Weekly and Three-Times-Weekly Dosings of Epoetin Alfa in Chemotherapy Patients: Problems of Study Design and Interpretation Tuan V. NguyenxTuan V. NguyenSearch for articles by this author , Giang N. TrinhxGiang N. TrinhSearch for articles by this author Show More Garvan Institute of Medical Research, Sydney, AustraliaMethodist Healthcare–Central Hospital, Memphis, TN https://doi.org/10.1200/JCO.2002.20.3.878 First Page Full Text PDF Figures and Tables © 2002 by American Society of Clinical Oncology
Aerobic exercise ameliorates cognitive function in older adults with mild cognitive impairment: a systematic review and meta-analysis of randomised controlled trials
Authors: Guohua Zheng, Rui Xia, Wenji Zhou, Jing Tao, Lidian Chen
Journal: British Journal of Sports Medicine (2016)

Objective To evaluate the effect of aerobic exercise on cognitive function in people with mild cognitive impairment (MCI). Design Systematic review and meta-analysis of aerobic exercise intervention for cognitive function in older adults with MCI. Data sources PubMed, EMBASE, SinoMed, China National Knowledge Infrastructure (CNKI), Wanfang and Chinese Science and Technology Periodical (VIP) databases from their inception to 31 January 2015, the Cochrane Central Register of Controlled Trials (Cochrane Library, 2015, Issue 3) and the reference lists of all retrieved articles. Eligibility criteria Randomised controlled trials, older adults with MCI, aerobic exercises compared with no specific exercise intervention for global cognitive ability and any specific domains of cognition. Data synthesis Meta-analysis was conducted with RevMan V.5.3 software using the fixed-effect model for the available data without significant heterogeneity, or the random-effect model was used if appropriate. Results 11 studies were identified involving 1497 participants. Meta-analysis showed that aerobic exercise significantly improved global cognitive ability (Mini-Mental State Examination (MMSE) scores: MD=0.98, 95% CI 0.5 to 1.45, p&lt;0.0001; Montreal Cognitive Assessment (MoCA) scores: MD=2.7, 95% CI 1.11 to 4.29, p=0.0009); weakly, positively improve memory (immediately recall: SMD=0.29, 95% CI 0.13 to 0.46, p=0.0005; delay recall: SMD=0.22, 95% CI 0.09 to 0.34, p=0.0005). No significant improvement was found in other domains of cognition. Conclusions Aerobic exercise led to an improvement in global cognitive ability and had a positive effect with a small effect size on memory in people with MCI. However, owing to the limitations of the included studies, these findings should be interpreted cautiously.