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1
Pomeroy, Caroline. "Ecological Identity: Becoming a Reflective Environmentalist, by Mitchell Thomashow. The Massachusetts Institute of Technology Press, 1995." Journal of Political Ecology 2, no. 1 (December 1, 1995): 47. http://dx.doi.org/10.2458/v2i1.20170.
Повний текст джерелаАнотація:
Ecological Identity: Becoming a Reflective Environmentalist, by Mitchell Thomashow. The Massachusetts Institute of Technology Press, 1995. 228 pp. Reviewed by Caroline Pomeroy, Institute of Marine Sciences, University of California, Santa Cruz.
2
Teng, Wen Li. "Grant Park and the Globe: Lucy Mitchell, Bessie Bennett, and the Art Institute of Chicago." Virginia Tech Undergraduate Historical Review 9, no. 1 (June 11, 2020): 17. http://dx.doi.org/10.21061/vtuhr.v9i0.3.
Повний текст джерела
3
French, D. H., and G. D. Summers. "Pre-Urartian and Urartian Pottery from the Muş Region." Anatolian Studies 44 (December 1994): 77–84. http://dx.doi.org/10.2307/3642984.
Повний текст джерелаАнотація:
The pottery discussed here was collected by C. A. Burney during his survey in 1956 and in 1965. We would like to express our thanks to Charles Burney for valuable discussion and for encouraging publication of the material. We have also profited from discussion with Drs. Ayşe Gürsan-Salzman, Mitchell Rothman, and A. G. Sagona. The opinions expressed are, however, our own. Richard Bayliss prepared the illustrations.The material from Tepeköy has not previously been published. Some of the other sherds appear in Russell's study (1980) and this has been indicated in the catalogue. All the sherds are stored in the British Institute of Archaeology at Ankara, each clearly marked.
4
Barrell, Ray, and Robert Metz. "An assessment of NIESR forecast accuracy." National Institute Economic Review 196 (April 1, 2006): 36–39. http://dx.doi.org/10.1177/0027950106067042.
Повний текст джерелаАнотація:
The Institute periodically reviews the accuracy of its macroeconomic forecasts. Pain et al. (2001) compare the performance of NIESR output forecasts to a naïve forecast that uses a simple rule to predict growth next year. They find that between 1980 and 2000 the National Institute forecast performed better than a naïve, or random walk, forecast in two years out of three. Poulizac et al. (1996) consider a sequence of quarterly economic forecasts published by NIESR between 1982 and 1995 (beginning with that produced in February for the growth of GDP and inflation in the following year and finishing with the forecast produced in November for growth in the current year). They show how the reliability of the Institute's forecast improves as the forecast horizon approaches and conclude that errors to GDP and inflation forecasts are normally distributed. In a similar vein, Mitchell (2005) shows that the Institute's point forecast of inflation is reliable whilst its measure of uncertainty has been exaggerated.
5
Davies, G. "Cremna in Pisidia: a re-appraisal of the siege works." Anatolian Studies 50 (December 2000): 151–58. http://dx.doi.org/10.2307/3643020.
Повний текст джерелаАнотація:
The only significant occasion that Cremna emerges from the shadows of historical obscurity is during its siege by Roman forces in the third century AD. Our sole surviving source for this incident is the account related by Zosimus which, despite covering two generous paragraphs of text, remains a collage of anecdotal observations of limited application to the student of siege operations. Notwithstanding the weaknesses of the literary evidence, an archaeological survey conducted with the assistance of the British Institute of Archaeology at Ankara in the mid 1980s, revealed that substantial elements of the Roman siege system still survived in situ. The recently published account of this survey (Mitchell et al 1995) presents a number of interesting arguments concerning the tactical role of these siege works and their relationship to the local topography. In the course of more general research into Roman siege works, the author undertook a field inspection of the site in September 1997 and would suggest that certain aspects of the published analysis require further refinement. This paper is intended to address these outstanding issues. The helpful comments made by Professors S Mitchell and J J Wilkes and Dr J J Coulton in respect of an earlier draft, are gratefully acknowledged.
6
Jernudd, Björn H. "LANGUAGE, EDUCATION AND SOCIETY IN A CHANGING WORLD.Tina Hickey and Jenny Williams (Eds.). Philadelphia: Multilingual Matters, 1996. Pp. viii + 287. $59.00 cloth." Studies in Second Language Acquisition 20, no. 1 (March 1998): 118–19. http://dx.doi.org/10.1017/s0272263198281058.
Повний текст джерелаАнотація:
This is a selection of papers from a conference hosted by the Irish Association for Applied Linguistics at the Marino Institute of Education in Dublin in June 1994. In an introductory paper, Rosamond Mitchell calls us to “defend and develop the professionalism of language teachers” (p. 17), which Mary Ruane amplifies to counter pessimism among language professionals arising from a feeling of a lack of control over “issues on a wider agenda” (p. 27). On the same theme, John Edwards calls for sociopolitical engagement with ethnic-minority-language situations (p. 34) and Helen Ó Murchú calls for empowerment of the “lesser used language communities” (p. 44) in a supportive response to Edwards' keynote address.
7
Mitchell, Stephen. "Ariassos 1990." Anatolian Studies 41 (December 1991): 159–72. http://dx.doi.org/10.2307/3642938.
Повний текст джерелаАнотація:
The survey of Ariassos, which we had begun in 1988, was completed between 24 August and 24 September 1990. The team members were Dr. Stephen Mitchell, Dr. Eddie Owens, Linda Keyes, and Ian Williams (University College of Swansea), Sabri Aydal (Antalya Museum). Ian Pollet and Danny Gysen (Leuven), Sarah Cormack (Yale), Armin Schulz (Münster), Claudia Rutherford (Oxford), and Yusuf Gül (Izmir Museum, representing the Turkish Department of Antiquities). Funds for the season were provided by the British Academy, the British Institute of Archaeology at Ankara, the Roman Society, and the Craven Committee. The student members of the group were also aided by travel grants from their various universities. The Institute at Ankara, as ever, provided invaluable logistic support, notably the use of a landrover, and I am particularly grateful to Chris Lightfoot for helping to arrange our accommodation before work began. Special thanks are due to our many friends in the small town of Bademaǧaç, notably to Ramazan Şener and his family and to Ayfer Orbay, our “landlady”.
8
Waelkens, Marc, Stephen Mitchell, and Edwin Owens. "Sagalassos 1989." Anatolian Studies 40 (December 1990): 185–98. http://dx.doi.org/10.2307/3642801.
Повний текст джерелаАнотація:
During 1989 the Pisidian survey project continued for its fifth season at Sagalassos. The survey was directed in the first half of the season by Dr. S. Mitchell (University College of Swansea) and in the second half by Prof. M. Waelkens (Catholic University of Leuven and National Fund for Scientific Research, Belgium). The team consisted of Prof. W. Viaene (geologist), Dr. M. Lodewijckx, R. Degeest, E. Scheltens, L. Vandeput, H. Bracke, A. De Daele, P. De Jonghe (Catholic University of Leuven, Belgium), Dr. E. Owens (University College of Swansea), Dr. Chr. Lightfoot (The British Institute of Archaeology at Ankara), Mr. R. Fursdon, R. Harrison and A. Young (topographers, University of Newcastle), and F. Richards (Sydney University). For 3 weeks we were joined by Selçuk Baser, director of the Museum of Burdur, who with M. Waelkens, directed a rescue excavation in the potters' quarter. Muhsin Endoǧru (Boǧazköy Museum) represented the Turkish Antiquities Department. The main financial support came from the National Fund for Scientific Research (Belgium), the Prime Ministry of the Flemish Community (Belgium), the Flemish Ministry of Education (Belgium), the British Academy and the British Institute of Archaeology at Ankara.
9
Smith, Tyler Jo. "Highland gods: rock-cut votive reliefs from the Pisidian Survey." Anatolian Studies 61 (December 2011): 133–50. http://dx.doi.org/10.1017/s0066154600008814.
Повний текст джерелаАнотація:
AbstractBetween 1982 and 1996 a group of rock-cut votive reliefs was discovered during archaeological survey in Pisidia under the direction of Stephen Mitchell and the sponsorship of the British Institute (of Archaeology) at Ankara. The types represented include a horseman deity, perhaps Kakasbos, the Dioscuri with ‘goddess’ and the moon-god Men. The reliefs are discussed according to their cults and iconography, and their contribution to art and religion both locally and beyond. As a religious phenomenon, they are further considered in relation to both regional traditions and empire-wide practices. It is suggested that reliefs of this type, that are associated with the protection of mortals, should also be viewed as part of the history of devotional art and added to discussions of rock art that extend beyond the Greek and Roman worlds. A detailed catalogue of the reliefs, organised by iconographic type, concludes the article.
10
Kubińska, Jadwiga. "Un Tombeau de Famille d'Ancyre de Galatie et la Question de TETPI.ΟΣΚΟΝ". Anatolian Studies 45 (грудень 1995): 233–36. http://dx.doi.org/10.2307/3642921.
Повний текст джерелаАнотація:
Le monument de marbre blanc avec l'inscription a été découvert par Monsieur D. H. French, directeur du British Institute of Archaeology at Ankara, dans le village de Buğduz (région d'Ankara) en octobre 1973. La photo de la pierre et la copie du texte ont été faites par lui (Pl. XXXIV).Le monument a été sûrement déplacé de son lieu d'origine et un jour remployé dans la fontaine où l'a vu French et où il semble être resté jusqu'à présent.L'inscription a été publiée par S. Mitchell qui a seulement défini la pierre portant l'épitaphe comme autel de marbre blanc cassé en deux morceaux a) et b) et en a donné les dimensions:a) haut. 0,93 m; larg. 0,61 m;b) haut. 1,47 m; larg. 0,62 m; épaiss. 0,33 m.La hauteur de la pierre est donc considérable, de 2,20 m. Pour cette raison sa définition comme autel nous semble douteuse. L'éditeur n'a pas publié de photo qui aurait permis de se faire une opinion propre sur ce monument.
11
Cole, Barry L. "Professor Donald E Mitchell The H Barry Collin Research Medallist 2012 Foundation Director of the National Vision Research Institute of Australia." Clinical and Experimental Optometry 96, no. 4 (July 2013): 433–35. http://dx.doi.org/10.1111/cxo.12081.
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12
Diefenbach, Catherine S., Fangxin Hong, Kevin A. David, Jonathon Cohen, Michael Robertson, Ranjana Advani, Neil D. Palmisiano, Richard F. Ambinder, Brad S. Kahl, and Stephen Ansell. "Title: A Phase I Study with an Expansion Cohort of the Combination of Ipilimumab and Nivolumab and Brentuximab Vedotin in Patients with Relapsed/Refractory Hodgkin Lymphoma: A Trial of the ECOG-ACRIN Cancer Research Group (E4412 Arms D and E)." Blood 128, no. 22 (December 2, 2016): 1106. http://dx.doi.org/10.1182/blood.v128.22.1106.1106.
Повний текст джерелаАнотація:
Abstract Background: Despite advances in chemotherapy, relapsed/refractory (R/R) Hodgkin lymphoma (HL) remains a significant clinical challenge and an unmet medical need. HL has a unique biology in which a small number of malignant Hodgkin Reed-Sternberg (HRS) cells propagate an immunosuppressive microenvironment. We hypothesized that using immune checkpoint inhibitor therapy to activate the immune cells in the tumor microenvironment, and concurrently targeting HRS cells with the CD30 antibody-drug conjugate brentuximab vedotin (BV), could overcome tumor cell resistance. E4412 is a Phase 1 ECOG-ACRIN sponsored study of the combination of BV and ipilimumab (IPI) and nivolumab (Nivo) in patients with R/R HL. Here we present the preliminary safety and response data on the patients treated with BV + Nivo (Arms D and E). Methods: Patients with confirmed R/R HL were treated with Nivo 3mg/kg and BV 1.2mg/kg (Arm D: Dose Level 1) or 1.8mg/kg (Arm E: Dose Level 2) in dose escalation with a 3+3 design and an expansion cohort (Arm F) of 9 patients. BV and Nivo are given every 21 days for 16 cycles; Nivo may be continued for an additional year (total 2 years of Nivo therapy). Dose limiting toxicity (DLT) was defined for purposes of dose escalation within the first cycle of therapy. Patients are followed for toxicity up to 30 days beyond their last treatment. Results: As of 7/20/2016 10 patients (1 ineligible) have been treated with BV + Nivo. We report the data on the dose escalation population: 3 patients: Arm D, 7 patients: Arm E. Data will be updated to include the full BV + Nivo dose escalation and dose expansion cohorts (Arms D, E & F) (N = 19) by the time of the Annual Meeting. Median age was 46; (range: 25-53). Six patients were male. Patients were heavily pretreated with a median of 3 prior therapies. Six patients had prior SCT (5 autologous, 1 allogeneic); 2patients had prior treatment with BV. Safety: Ten of 10 patients are evaluable for safety. Overall safety profiles show that the regimen of BV + Nivo was extremely well tolerated. One patient out of 7 in dose level 2 experienced a DLT (pneumonitis grade 3 with grade 3 dyspnea and hypoxia, and typhilits grade 3), this patient had received a prior SCT, and made a full recovery from his toxicities. Per protocol he discontinued further therapy. No other DLTs were noted for the remaining 9 patients. Common and relevant toxicities considered at least possibly related to drug during any cycle of treatment are shown in Table 1. There were no Grade 4 treatment related adverse events (AEs). The only additional grade 3 AEs noted were one each grade 3 rash and puritis. The most common grade 1-2 treatment related adverse events were: transaminitis (9), peripheral sensory neuropathy (6), and rash (3). Other AEs of interest included: diarrhea (3), blurry vision (2), and myalgias (2). One grade 1-2 infusion reaction was noted, this patient was able to receive subsequent therapy with pre-medication. Response: Eight of 10 patients are evaluable for response. One patient is not yet evaluable. For the 8 evaluable patients the overall response rate (ORR) for the combination of BV + Nivo was 100%, with a CR rate of 62.5% (5/8), with 95% CI of 0.25-0.91. One patient was ineligible for laboratory studies that were out of range at screening, however this patient continues on therapy, and also had a response. One of 5 CRs occurred at in dose level 1 (BV 1.2 mg/kg). Both patients who had been treated with prior BV achieved CRs. The progression free survival (PFS) to date is 100% with a median follow-up of 0.3 years. Conclusion: In this first reported study of the combination of the checkpoint inhibitor Nivo and the ADC BV therapy was well tolerated with one DLT, and primarily grade 1 and 2 toxicities. In a heavily pretreated patient population, 20% of whom had had prior BV and 60% of whom were s/p ASCT, the ORR of 100% and CR rate of 62.5% suggests a deepening of response compared to either therapy alone. Optimization of this combination strategy is planned with ongoing accrual to cohorts receiving BV + Nivo, and BV + Ipi + Nivo. Data will be updated to include the full BV + Nivo cohort (N = 19) by the time of the Annual Meeting. Disclosures Diefenbach: Seattle Genetics: Consultancy, Honoraria, Research Funding; BMS: Consultancy, Research Funding; Merck: Research Funding; Genentech: Research Funding; Incyte: Research Funding; LAM Therapeutics: Research Funding; Molecular Templates: Research Funding; Oncomed: Research Funding; This study was coordinated by the ECOG-ACRIN Cancer Research Group (Robert L. Comis, MD and Mitchell D. Schnall, MD, PhD, Group Co-Chairs) and supported by the National Cancer Institute of the National Institutes of Health under the following award number: Research Funding. Hong:This study was coordinated by the ECOG-ACRIN Cancer Research Group (Robert L. Comis, MD and Mitchell D. Schnall, MD, PhD, Group Co-Chairs) and supported by the National Cancer Institute of the National Institutes of Health under the following award number: Research Funding. Cohen:Seattle Genetics: Consultancy, Honoraria, Research Funding; BMS: Research Funding. Advani:Stanford University: Employment; Juno: Consultancy, Honoraria; BMS: Consultancy, Honoraria, Research Funding; Spectrum: Consultancy, Honoraria; Sutro: Consultancy, Honoraria; Genentech: Consultancy, Honoraria, Research Funding; Kura: Research Funding; Merck: Research Funding; Celgene: Research Funding; Janssen: Research Funding; Seattle Genetics: Research Funding; Regeneron: Research Funding; Agensys: Research Funding; Pharmacyclics: Research Funding; Infinity: Research Funding; Millennium: Research Funding; FortySeven: Consultancy, Honoraria; Kyowa Hakko Kirin: Consultancy, Honoraria. Kahl:This study was coordinated by the ECOG-ACRIN Cancer Research Group (Robert L. Comis, MD and Mitchell D. Schnall, MD, PhD, Group Co-Chairs) and supported by the National Cancer Institute of the National Institutes of Health under the following award number: Research Funding. Ansell:BMS, Seattle Genetics, Merck, Celldex and Affimed: Research Funding.
13
Mitchell, Stephen, Edwin Owens, and Marc Waelkens. "Ariassos and Sagalassos 1988." Anatolian Studies 39 (December 1989): 63–77. http://dx.doi.org/10.2307/3642813.
Повний текст джерелаАнотація:
During 1988 the Pisidian survey project continued at a new site, Ariassos, and for a fourth season at Sagalassos. The team, directed at Ariassos by Dr. S. Mitchell and at Sagalassos by Professor M. Waelkens (Dept. of Archaeology, Catholic University of Leuven, Research Associate of the National Fund for Scientific Research (Belgium)) consisted of Bay Sabri Aydal of Antalya Museum (topographer), Dr. E. Owens, Y. Day, and A. Millard (University College of Swansea), S. Cormack (Yale University), Dr. M. Lodewijckx, R. Degeest, L. Vandeput, and C. Nuitjen (University of Leuven), D. Roberts, R. Johnson, and S. Corker (University of Newcastle), A. Schulz and D. Pohl (University of Münster), and Osman Ermişler (Konya Museum), who represented the Turkish Antiquities Department. The main financial support for Ariassos came from the British Academy and the British Institute of Archaeology at Ankara, and for Sagalassos from the National Fund for Scientific Research (Belgium) and from the Flemish Ministry of Education (Belgium). Thanks are due to the Eski Eserler ve Müzeler Genel Müdürlüǧü, who gave permission for the survey and provided surveying equipment, to the staff of the Emniyet Müdürlüǧü in Antalya and in Burdur, and to the Belediye officials and the inhabitants of Bademaǧacı and of Aǧlasun.
14
Mitchell, Stephen, and Marc Waelkens. "Sagalassus and Cremna 1986." Anatolian Studies 37 (December 1987): 37–47. http://dx.doi.org/10.2307/3642889.
Повний текст джерелаАнотація:
A second season of survey work at Sagalassus and Cremna in Pisidia was started on 2 July and continued until 12 August 1986. This was the most recent instalment of a project to carry out detailed archaeological and architectural studies of the surviving remains of the Graeco–Roman cities of this region. Between 1982 and 1984 we had worked at the Roman colony of Pisidian Antioch, and a final report is nearing completion. In 1985, we began at Cremna, another Roman colony, with the intention of complementing the excavation of the site carried out in the early 1970s by a team from Istanbul University led by Professor Jale İnan, and also spent a few days of preliminary reconnaissance at the metropolis of Roman Pisidia, Sagalassus (see AS. XXXVI, 1986, 8–10). All the field work has been funded by the British Academy, the British Institute of Archaeology at Ankara, the Roman Society, and the Craven Committee of Oxford University. In 1986 the team worked at Sagalassus until 24 July, thereafter we were at Cremna. The participants were Dr. Stephen Mitchell, Dr. Marc Waelkens, Dr. Gregory Horsley, Dr. Edwin Owens, Mr. Robin Fursdon (chief surveyor), Roger Bruton, Mark Critchley, Helen Thackray (student surveyors), Roger and Miranda McKearney.
15
Urban, Eva. "Multilingual Theatre in Brittany: Celtic Enlightenment and Cosmopolitanism." New Theatre Quarterly 34, no. 3 (July 13, 2018): 283–97. http://dx.doi.org/10.1017/s0266464x1800026x.
Повний текст джерелаАнотація:
In this article Eva Urban describes a historical tradition of Breton enlightenment theatre, and examines in detail two multilingual contemporary plays staged in Brittany: Merc’h an Eog / Merch yr Eog / La Fille du Saumon (2016), an international interceltic co-production by the Breton Teatr Piba and the Theatr Genedlaethol Cymru (the Welsh-language national theatre of Wales); and the Teatr Piba production Tiez Brav A Oa Ganeomp / On avait de jolies maisons (2017). She examines recurring themes about knowledge, enlightenment journeys, and refugees in Brittany in these plays and performances, and presents the argument that they stage cosmopolitan and intercultural philosophical ideas. Eva Urban is Senior Research Fellow at the Senator George J. Mitchell Institute for Global Peace, Security and Justice, Queen's University Belfast. She has held a Région de Bretagne Postdoctoral Research Fellowship at the Centre for Breton and Celtic Studies, University of Rennes 2, a research lectureship in the English Department, University of Rennes 2, and a British Academy Postdoctoral Fellowship at the University of Cambridge. She is the author of Community Politics and the Peace Process in Contemporary Northern Irish Drama (Peter Lang, 2011) and has published articles in New Theatre Quarterly, Etudes Irlandaises, Caleidoscopio, and chapters in book collections.
16
Nym Mayhall, Laura E. "BOOK REVIEW: Edited by Vanessa Toulmin, Simon Popple, and Patrick Russell.THE LOST WORLD OF MITCHELL & KENYON: EDWARDIAN BRITAIN ON FILM. London: British Film Institute, 2004." Victorian Studies 48, no. 3 (April 2006): 560–62. http://dx.doi.org/10.2979/vic.2006.48.3.560.
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Mitchell, Stephen, and Marc Waelkens. "Cremna and Sagalassus 1987." Anatolian Studies 38 (December 1988): 53–65. http://dx.doi.org/10.2307/3642841.
Повний текст джерелаАнотація:
The survey of these two sites was resumed on 1 July 1987. The Cremna season, directed by Stephen Mitchell, ran until 25 July; from 27 July to 20 August the team worked at Sagalassus under Marc Waelkens. The other participants were Mustafa Büyükkolancı, Sarah Cormack, Christopher Lightfoot and Edwin Owens (archaeologists), William Hargrove and Claire Robinson (student assistants), Anthea Cudworth, Robin Fursdon, Duncan Mallace, and Mark Willy (surveyors), Greg Horsley (epigraphist), and Kirsty Norman (conservator). Our representative was Sabri Aydal of Antalya Museum, who also provided valuable and expert assistance to the surveyors. We are grateful, as in previous seasons, to many local people for help and support: to Selçuk Başer, Ali Harmankaya and the staff of the Burdur Museum; to the officers of the Emniyet Müdürlüǧü at Burdur and of the Jandarma at Bucak and Aǧlasun; to the villagers at Çamlık, and to Sabit Kaya, Kaymakam of Aǧlasun, who provided us with accommodation. The work was funded by the British Academy, the British Institute of Archaeology at Ankara, the Craven Committee of Oxford University, the Roman Society, and the National Fund for Scientific Research (Belgium). Above all we are grateful to the Director General of Antiquities and Museums in Turkey, Nurettin Yardımcı, and to his staff, especially to Nimet Berkok and Mustafa Karahan, for granting permission for the survey and for much other assistance.
18
Borst, Piet. "Edward Charles Slater. 16 January 1917 — 26 March 2016." Biographical Memoirs of Fellows of the Royal Society 63 (January 2017): 527–51. http://dx.doi.org/10.1098/rsbm.2016.0024.
Повний текст джерелаАнотація:
With the death of Edward Charles Slater, Bill for insiders, biochemistry loses one of the key players in the field of bioenergetics in the second half of the twentieth century. Raised in Australia and trained as a chemist, he joined the lab of David Keilin FRS in Cambridge for his PhD where he discovered a new component of the mitochondrial respiratory chain, an Fe-S protein, long known as the Slater factor. After a brief post-doc period in the lab of Severo Ochoa in New York, where Slater started studies on oxidative phosphorylation that would remain his major interest, he returned to Keilin's institute. In 1953 he formulated there his chemical hypothesis for the mechanism of oxidative phosphorylation that would dominate the field until displaced by the chemi-osmotic theory of Peter Mitchell FRS. In 1955 Slater moved to Amsterdam, The Netherlands, where he built up one of the largest and most successful biochemistry labs in Europe. He was not only an excellent biochemist, but also an outstanding mentor and a gifted administrator who turned Biochimica et Biophysica Acta ( BBA ) into the largest and one of the most influential biochemical journals of the 1960s and 1970s and who contributed to the governance of numerous organizations, such as the International Union of Biochemistry and Molecular Biology (IUBMB).
19
Knox, David M. "A Ramble through the Actuarial Countryside: The Collected Papers, Essays and Speeches of Frank Mitchell Redington. Edited by Chamberlin Gary. (Institute of Actuaries Students' Society, London, 1986.)." Journal of the Staple Inn Actuarial Society 30 (December 1987): 231–33. http://dx.doi.org/10.1017/s0020269x00010203.
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Subramaniam, Hari, and Alex J. Mitchell. "The prognosis of depression in late life versus mid-life: implications for the treatment of older adults." International Psychogeriatrics 17, no. 4 (October 25, 2005): 533–38. http://dx.doi.org/10.1017/s1041610205002437.
Повний текст джерелаАнотація:
Depression in late life is extremely common. Of those aged 65 years or older, 2–5% have syndromal depression, but up to 20% of elderly people have depressive symptoms (Horwath et al., 2002). Both syndromal and subsyndromal depression carry a high risk of long-term complications and both are associated with elevated risks of morbidity and mortality (Penninx et al., 1999). Despite repeated alerts, depression is consistently under-recognized in acute medical settings, in nursing homes and in primary care (Volkers et al., 2004). For reasons that are inadequately understood, late-life depression seems to be under-treated to an even greater extent than depression in mid-life (Mackenzie et al., 1999). This issue is particularly important, given that effective and safe treatments for depression are available (Bartels et al., 2003), even though the evidence regarding maintenance therapies in older people is inconsistent (Geddes et al., 2003; Wilson et al., 2003). Recent evidence suggests that a package of care can improve the care of older depressed patients in primary care settings (Bruce et al., 2004) and in nursing homes (Ciechanowski et al., 2004). This has led to the development of several clinical guidelines specifically for late-life depression (Baldwin et al., 2003; Charney et al., 2003; Lebowitzet al., 1997). Yet, in the recent National Institute of Clinical Excellence (NICE) guidelines for the management of depression in primary and secondary care, no distinction was made between early, middle and late-life depression (Malone and Mitchell, 2005).
21
Ketola, Tarja. "Companies in a World of Conflict. edited by John Mitchell, 1998. The Royal Institute of International Affairs and Earthscan, xiv+192 pp, £16.95 (pbk). ISBN 1‐85383‐536‐6." Business Strategy and the Environment 8, no. 3 (May 1999): 200–201. http://dx.doi.org/10.1002/(sici)1099-0836(199905/06)8:3<200::aid-bse201>3.0.co;2-a.
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FitzGerald, Lisa, Eva Urban, Rosemary Jenkinson, David Grant, and Tom Maguire. "Human Rights and Theatre Practice in Northern Ireland: A Round-Table Discussion." New Theatre Quarterly 36, no. 4 (November 2020): 279–91. http://dx.doi.org/10.1017/s0266464x20000664.
Повний текст джерелаАнотація:
This round-table discussion, edited by Eva Urban and Lisa FitzGerald, took place on 5 July 2019 as part of the conference ‘New Romantics: Performing Ireland and Cosmopolitanism on the Anniversary of Human Rights’ organized by the editors at the Brian Friel Theatre, Queen’s University Belfast. Lisa FitzGerald is a theatre historian and ecocritic who completed postdoctoral fellowships at the Centre de Recherche Bretonne et Celtique (CRBC), Université Rennes 2 and the Rachel Carson Centre for Environment and Society, Ludwig Maximilian University of Munich. She is the author of Re-Place: Irish Theatre Environments (Peter Lang, 2017) and Digital Vision and the Ecological Aesthetic (forthcoming, Bloomsbury, 2020). Eva Urban is a Senior Research Fellow at the Senator George J. Mitchell Institute for Global Peace, Security, and Justice, Queen’s University Belfast, and an Associate Fellow of the Institute of Irish Studies, QUB. She is the author of Community Politics and the Peace Process in Contemporary Northern Irish Drama (Peter Lang, 2011) and La Philosophie des Lumières dans le Théâtre Breton: Tradition et Influences (Université de Rennes, 2019). Rosemary Jenkinson is a Belfast playwright and writer of five short story collections. Her plays include The Bonefire (Rough Magic), Planet Belfast (Tinderbox), White Star of the North, Here Comes the Night (Lyric), Lives in Translation (Kabosh Theatre Company), and Michelle and Arlene (Accidental Theatre). Her writing for radio includes Castlereagh to Kandahar (BBC Radio 3) and The Blackthorn Tree (BBC Radio 4). She has received a Major Individual Artist Award from the Arts Council of Northern Ireland to write a memoir. Tom Maguire is Head of the School of Arts and Humanities at Ulster University and has published widely on Irish and Scottish theatre and in the areas of Theatre for Young Audiences and Storytelling Performance. His heritage research projects include the collection Heritage after Conflict: Northern Ireland (Routledge, 2018, co-edited with Elizabeth Crooke). David Grant is a former Programme Director of the Dublin Theatre Festival and was Artistic Director of the Lyric Theatre in Belfast. He has worked extensively as a theatre director throughout Ireland and is co-investigator of an AHRC-funded research project into Arts for Reconciliation. He lectures in drama at Queen’s University Belfast.
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Sherlock, E. B. O. "A Ramble Through The Actuarial Countryside: The Collected Papers. Essays and Speeches of Frank Mitchell Redington M.A. Edited By Gary Chamberlin M.A. (Published by the Institute of Actuaries Students' Society.)." Journal of the Institute of Actuaries 113, no. 3 (December 1986): 525–27. http://dx.doi.org/10.1017/s0020268100042608.
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Liesegang, Thomas J. "Human DNA repair genes. Wood RD,∗∗University of Pittsburgh Cancer Institute, S867 Scaife Hall, 3550 Terrace Street, Pittsburgh, PA 15261. Mitchell M, Sgouros J, Lindahl T. Science 2001;291:1284–1289." American Journal of Ophthalmology 132, no. 2 (August 2001): 298. http://dx.doi.org/10.1016/s0002-9394(01)01079-0.
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BROWN, JEFFREY, STEVEN HABERMAN, MOSHE MILEVSKY, and MIKE ORSZAG. "Overview of the Issue." Journal of Pension Economics and Finance 1, no. 3 (November 2002): 193–95. http://dx.doi.org/10.1017/s1474747202001154.
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This is the final issue of the first volume of the Journal of Pension Economics and Finance. We are pleased that the Journal has had a very successful first year, both in terms of the quality of submissions and in terms of building up an extensive and high quality subscription base. We will report in more detail on our first year as well as our plans for the future in the first issue of the second volume.The four articles in this issue span a broad range of topics. The first article is by David McCarthy (Oxford University, Institute of Ageing), Olivia Mitchell (University of Pennsylvania, Pension Research Council) and John Piggott (University of New South Wales, Centre for Pensions and Superannuation) who have written a paper entitled: Asset rich and cash poor: retirement provision and housing policy in Singapore.As mandatory defined contribution systems are increasingly adopted around the world, the experience in Singapore is particularly relevant in that its Central Provident Fund (CPF) is one of the oldest major international examples of a mandatory defined contribution pension system. With funds representing roughly 60% of Singapore's GDP, the CPF is also one of the most prominent publicly managed investment funds in the world.The particular focal point of the McCarthy et al. paper is the effect of rules in Singapore which allow individuals to use their accumulated funds to pay for housing. The use of retirement savings vehicles for approved purposes, such as medical care, education and unemployment, is an important policy issue, with most countries continuing to have strict prohibitions on drawing funds prior to retirement.
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Bakitas, Marie, J. Nicholas Dionne-Odom, Maria Pisu, Dilip Sankar Babu, Tasha Smith, Imatullah Akyar, and Lisa Zubkoff. "Measuring implementation of early, concurrent palliative care in community settings." Journal of Clinical Oncology 33, no. 29_suppl (October 10, 2015): 145. http://dx.doi.org/10.1200/jco.2015.33.29_suppl.145.
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145 Background: ASCO recommends “…combined standard oncology and palliative care…early in the course of illness for any patient with metastatic cancer and/or high symptom burden”. Few settings have implemented this recommendation and rural community cancer centers (CCC) are particularly disadvantaged due to scarce palliative care (PC) resources. The evidenced-based ENABLE (Educate, Nurture, Advise, Before Life Ends) early concurrent PC intervention has demonstrated efficacy and benefit for rural patients and caregivers and we are implementing ENABLE using a virtual learning collaborative funded by the American Cancer Society. Since no PC-specific implementation measures exist, one of our primary efforts has been instrument development. Methods: This Implementation Study includes 4 racially-diverse CCCs: Gibbs Cancer Center, Spartanburg, SC; Mitchell Cancer Institute, Mobile, AL; Birmingham VAMC; and Gyn Oncology/University of Alabama at Birmingham. The project aims are to: 1. Build an interactive research community to assess sites’ institutional structure and PC resources; and 2. Evaluate pre- and post-ENABLE implementation using RE-AIM (Reach, Effectiveness, Adoption, Implementation, and Maintenance) framework. An expert panel assisted with implementation measure development specific to ENABLE’s essential elements. Instruments include: the General Organizational Index, the RE-AIM Assessment Tool, Oncology Providers Perceptions of Early Concurrent PC, and Implementation Costs. Results: All measures were found to have face and content validity. Feasibility and inter-rater reliability were determined during pilot-testing. Data, (housed in a REDCap database), have been collected using face-to-face interviews and web-based platforms over 2 cycles of pre- and post-implementation site visits. Measurement challenges include: 1. Inconsistent IRB interpretation of implementation science practices; 2. Limited implementation resources (space, staff, and time); and 3. Difficulties with centralized data collection. Conclusions: Valid measures are critical to determine implementation success. We will present implementation measures (Toolkit) and examples of outcome data.
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Heilbronner, Edgar. "Biographical Encyclopedia of Scientists. Herausgegeben vonJ. Daintith, S. Mitchell, E. Tootill undD. Gjertsen. Institute of Physics Publishing, Bristol (USA), 1994. 2 Bände, zusammen 1075 S., geb. 95.00 £. - ISBN 0-7503-0287-9." Angewandte Chemie 107, no. 22 (November 17, 1995): 2773–74. http://dx.doi.org/10.1002/ange.19951072239.
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Jones, Richard. "Book Review: John V. Mitchell and Daniel Yergin (eds.), Companies in a World of Conflict: NGOs, Sanctions and Corporate Responsibility (London: Earthscan and The Royal Institute for International Affairs, 1998, 256 pp., £16.95 pbk.)." Millennium: Journal of International Studies 28, no. 2 (June 1999): 437–39. http://dx.doi.org/10.1177/03058298990280020422.
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Zymomria, Mykoła. "The Rules of How Reality Works Through the Prism of Post-Postmodern Prose." Czytanie Literatury. Łódzkie Studia Literaturoznawcze, no. 9 (December 30, 2020): 347–54. http://dx.doi.org/10.18778/2299-7458.09.18.
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The reviewer analyses the monograph Problematic-Thematic Units and Philosophical-Esthetical Parameters of the British Post-Postmodern Novel (Kyiv, 2020) written by Dmytro Drozdovskyi, a Ukrainian scholar from Taras Shevchenko Institute of Literature of the National Academy of Sciences of Ukraine, member of The European Society for the Study of English (Bulgarian branch). In the monograph, the author has outlined the theory of the post-postmodern novel based on the analysis of the key novels of contemporary British fiction (David Mitchell, Ian McEwan, Sarah waters, Mark Haddon, etc.). The review states that the Ukrainian scholar has developed the theory proposed by Fredric Jameson regarding the post-postmodern features of Cloud Atlas and also discusses the concept of meta-modernity as one of the sections in the post-postmodern literary paradigm in the UK. Drozdovskyi argues that meta-modernism cannot be the only term that explains all the peculiarities of contemporary British fiction, which also cannot be outlined as meta-modern but as post-postmodern. The scholar provides a new theory of the novel based on the exploitation of real and unreal historical facts and imagined alternative histories and multifaceted realities. Furthermore, the reviewer pays attention to the contribution this monograph has for world literary studies spotlighting the theory of literary meta-genre patterns, as Drozdovskyi provides a theory according to which literary periods can be divided into those in which the carnival is the dominant meta-genre pattern (like postmodernism) and those that exploit the mystery as the meta-genre pattern (post-postmodernism). The reviewer analyses the key thematic units explained by Drozdovskyi as the key ones that determine the semiosphere of the contemporary British novel (post-metaphysical and post-positivist thinking of the characters, medicalisation of the humanitarian discourse, and the representation of the temporal unity of different realities). The scholar also states that the post-postmodern British novel exploits the findings of German Romanticism and Kant’s philosophy.
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Marasas, W., W. Gelderblom, G. Shephard, and H. Vismer. "Mycotoxicological research in South Africa 1910-2011." World Mycotoxin Journal 5, no. 1 (February 1, 2012): 89–102. http://dx.doi.org/10.3920/wmj2011.1322.
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The British mycologist, I.B. Pole-Evans, was appointed as the first South African government mycologist in 1905 following the Anglo-Boer War (1899-1902). The Onderstepoort Veterinary Research Institute was founded in 1908 with the Swiss veterinarian, Arnold Theiler, as the first director. Thus, the stage was set for the commencement of mycotoxicological research when the Union of South Africa came into being in 1910. The first accounts of this pioneering research appeared in the 'Seventh and eight reports of the Director of Veterinary Research, Union of South Africa. 1918' in which D.T. Mitchell reported on the experimental reproduction of the neurotoxic syndrome, diplodiosis, in cattle with pure cultures of Stenocarpella maydis (= Diplodia zea) isolated by P.A. Van der Bijl and grown on sterile maize kernels. This is the first report of the experimental reproduction of a veterinary mycotoxicosis with a pure culture of a fungus in South Africa and possibly in the world. This seminal research was followed by a great deal of multidisciplinary research on veterinary mycotoxicoses as well as human syndromes in which fungal toxins are suspected to be involved, taxonomy of mycotoxigenic fungi and chemistry of mycotoxins in South Africa. The mycotoxicoses studied in South Africa include the following (more or less in chronological order): diplodiosis, Paspalum staggers, aflatoxicosis, human hepatocellular carcinoma, ochratoxicosis, lupinosis, facial eczema, tremorgenic mycotoxicosis, hyperoestrogenism, stachybotryotoxicosis, ergotism, leukoencephalomalacia and human oesophageal cancer. A major breakthrough in mycotoxicological research was made in South Africa in 1988 with the isolation and chemical characterisation of the carcinogenic fumonisins produced by Fusarium verticillioides in maize. Current research at the PROMEC Unit of the South African Medical Research Council on the risk assessment of fumonisins and intervention methods to reduce fumonisin intake by rural populations on a maize staple diet is highlighted. This paper concludes with a selected list of mycotoxicological publications by South African mycologists/plant pathologists, veterinarians and chemists/biochemists.
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Alsayed, Alhareth, Ashish Manne, Daisy E. Escobar, Gaurav Sharma, Pranitha Prodduturvar, and Omar Alkharabsheh. "Predictors of immune-related adverse events associated with checkpoint inhibitors." Journal of Clinical Oncology 38, no. 15_suppl (May 20, 2020): e15159-e15159. http://dx.doi.org/10.1200/jco.2020.38.15_suppl.e15159.
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e15159 Background: Immune-related adverse events (irAE) remain a significant challenge with the expansion of checkpoint inhibitors (ICI) indications. Unlike previous studies published, we investigated risk factors for irAE development, including lymphocytes and neutrophils counts in lung cancer and melanoma treated with all available ICIs in current clinical practice. Methods: This is a retrospective study conducted at the University of South Alabama Mitchell Cancer Institute. Between 2015-2019. A total of 160 patients with a diagnosis of melanoma (N = 54) or lung cancer (N = 106) who received at least two doses of ICI including ipilimumab (15%), nivolumab (32%), pembrolizumab (35%), dual nivolumab/ipilimumab (5%), durvalumab (9%) and atezolizumab (4%). The patient's baseline characteristics were extracted with irAE (grade 3/4) details and survival outcomes. Descriptive statistics were used, Fisher exact test to compare categorical variables, and Wilcoxon rank sum test for continuous variables using JMP software. Results: The median age at diagnosis was 64 years (range 17-93), with 51% females. Race distribution with 76% Caucasians and 26% African Americans. Around 30% of the cohort was treated for recurrence, and 39% did receive prior systemic chemotherapy. Median overall survival (OS) was 13.5 months (m) for melanoma and 16 m for lung cancer with CI 95% [16-24] and [15-23], respectively. Twenty-nine (29%) percent of the cohort (N = 46) had grade 3/4 irAEs. Median of baseline hematological parameters including total white blood count (WBC), absolute neutrophil count (ANC), absolute lymphocyte count (ALC), ANC to ALC ratio, and platelet to ALC ratio of these patients were not statistically different from the cohort without grade 3/4 irAEs. Interestingly, if a patient has baseline ALC < 1K/μL, the risk of irAE recurrence is low when ICI is re-initiated, p = .0143 (after symptomatic recovery from irAEs). Conclusions: Irrespective of ICI used, baseline lymphocyte count, and its relation to other blood counts have no clear impact on irAE. Larger cohorts or prospective studies are needed to make stronger conclusions about the relationship between the immune system and the occurrence of irAEs
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McGowen, Chelsea L., Nicole E. Caston, Sheila K. McElhany, Bryanna E. Diaz, Carrie C. McNair, Jeffrey Franks, Courtney J. Andrews, et al. "Trajectory of symptoms reported in remote symptom monitoring over the course of oncology treatment for gynecologic cancers." Journal of Clinical Oncology 40, no. 28_suppl (October 1, 2022): 270. http://dx.doi.org/10.1200/jco.2022.40.28_suppl.270.
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270 Background: Patients now have the ability to utilize electronic patient reported outcomes (ePROs) for remote symptom monitoring (RSM). This analysis seeks to better understand trajectory of reported symptoms during treatment for patients with gynecologic cancer participating in RSM. Methods: We approached patients with gynecological cancer initiating treatment at the Mitchell Cancer Institute (MCI) between 7/1/21-4/30/2022. Patients were eligible if they were starting chemotherapy, targeted therapy, or immunotherapy for a new cancer. Patients seeking a second opinion were excluded. Enrolled patients received symptom survey (PRO-CTCAE questions) via text or email once per week. Initially, only severe alerts were forwarded to the clinical care team; moderate alerts were forwarded to clinical teams once they were comfortable with alert management. Patients completed symptom assessments for 24 weeks or until withdrawal. Patient age at enrollment, race, sex, cancer type, cancer stage, and PROs were abstracted from electronic health records and the PRO platform (Carevive). Descriptive statistics were calculated using frequencies and percentages for categorical variables and median and interquartile ranges (IQR) for continuous variables. Results: A total of 60 female patients with gynecological cancer were enrolled; 33% were Black or African American and 67% were White; median age was 61 years (IQR 53-68). Seventy-eight percent (47/60) of patients reported 379 symptoms with at least one moderate or severe alert during this time period; 32% considered moderate and 68% considered severe. Overall, the most frequently reported symptom was pain (29%). At baseline (week 0), 14% and 41% of 56 patients reported moderate symptoms and severe symptoms, respectively. Symptom burden decreased over time with 4% and 7% of 27 patients who completed a survey at 12 weeks reporting moderate and severe symptoms. Specific symptom trajectories followed similar patterns. Conclusions: In our sample, patients reported the majority of symptoms during the first three months of treatment. Symptom trajectory decreased with time, suggesting symptoms are being effectively monitored and addressed by the clinical teams engaging in RSM. Future research is needed to understand if symptom improvement translates to increased quality of life, decreased hospitalizations, and increased survival for patients, as well as lessen the burden of call volume on the clinical team.
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Manne, Ashish, Madhuri S. Mulekar, Daisy E. Escobar, Pranitha Prodduturvar, Yazan Fahmawi, Phillip Henderson, Osama Abdul-Rahim, et al. "Compliance to the American Association for the Study of Liver Diseases (AASLD) guidelines and its impact on overall survival in patients with hepatocellular carcinoma." Journal of Clinical Oncology 38, no. 15_suppl (May 20, 2020): e16609-e16609. http://dx.doi.org/10.1200/jco.2020.38.15_suppl.e16609.
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e16609 Background: The Barcelona-Clinic Liver Cancer (BCLC) staging based management proposed by AASLD depends on baseline liver function and performance status of the patient in addition to tumor characteristics. Low adherence to AASLD guidelines, especially in advanced staged tumors, can be ascribed to suboptimal revision/updates of the guidelines reflecting the advancements in hepatocellular carcinoma (HCC) management. Here, in addition to the adherence rate, we explored the overall survival of patients with HCC according to first-line treatment modality compliance to AASLD guidelines. Methods: This is a retrospective study conducted at the University of South Alabama/Mitchell Cancer Institute. Between 2017 and 2019, 148 unique treatment-naïve patients with HCC were identified. Patients were staged according to the BCLC staging system and their compliance with suggested first-line treatment modality according to AASLD guidelines was noted. Overall survival was explored and differences between overall survival rates of compliant and non-complaint patients were compared using the log-rank Wilcoxon test. Results: In our cohort, the median age was 72.5 years (range 38-90). Males represented 80%. Caucasians, African Americans, and other ethnicities (e.g. Asians) represented 68%, 30% and 2% respectively. The overall adherence rate was 83%. The adherence rate according to BCLC stage 0, A, B, C and D was 100%, 97%, 77%, 77% and 38% respectively. Compliance vs. non-compliance to AASLD guidelines showed no significant difference in overall survival of patients with BCLC stage 0-A, B and C. In patients with BCLC stage D (N = 13), compared to patients treated in compliance to AASLD guidelines (N = 5), patients treated in non-compliance (N = 8) had better overall survival (2.2 vs. 5.2 months, p = 0.0012). Conclusions: In our cohort, the adherence rate to AASLD treatment guidelines in patients with BCLC stage D was very low at 38%. Lack of adherence in this group of patients translated into better overall survival. The current AASLD guidelines for the management of HCC have several limitations, especially for advanced stages. In the last few years, the FDA approved several tyrosine kinase inhibitors, immune checkpoint inhibitors and the monoclonal antibody, ramucirumab. This expansion generated the need for periodic updates/revisions of consensus guidelines.
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Manne, Ashish, Wadad Mneimneh, Osama Elkadi, Daisy E. Escobar, James Coley, Gabriel Bolanos Guzman, Sameeta Moh'd Fnu, Omar Alkharabsheh, and Moh'd M. Khushman. "The pattern of mucin 5AC (MUC5AC) expression using immunohistochemistry and its prognostic significance in patients with pancreatic ductal adenocarcinoma." Journal of Clinical Oncology 38, no. 15_suppl (May 20, 2020): e16756-e16756. http://dx.doi.org/10.1200/jco.2020.38.15_suppl.e16756.
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e16756 Background: Mucin-5AC (MUC5AC) is a secreted form of mucin. Its expression correlates with poor outcome in uterine, ampullary adenocarcinoma and cholangiocarcinoma. Its prognostic significance in pancreatic ductal adenocarcinoma (PDAC) is not well established. Here, we explored the pattern of MUC5AC expression using immunohistochemistry (IHC) and its prognostic significance in patients with PDAC. Methods: This is a retrospective study conducted at the University of South Alabama/Mitchell Cancer Institute. Between 2015-2019, 218 patients with PDAC were identified. Among this cohort, only 45 patients had tissue available for MUC5AC IHC staining. Two pathologists in- dependently scored the expression of MUC5AC. Staining percentage was estimated in 10% increments. Unpaired t test and log-rank Wilcoxon tests were used for statistical analysis. Results: In our cohort, the median age was 65 years (42-85). Males represented 55%. Caucasians, African Americans and other ethnicities (e.g. Asians) represented 71%, 25% and 4% respectively. Twenty patients (44%) had metastatic stage IV disease and 25 patients (56%) had non-metastatic disease. Positive cytoplasmic and apical MUC5AC expression by IHC was seen in 82% and 80% of patients respectively. The median apical MUC5AC expression was higher in metastatic patients compared to non-metastatic patients (67.5 % vs 30%, p = 0.0187 ) while there was no difference in the median cytoplasmic MUC5AC expression between metastatic and non-metastatic patients (13.7 % vs 12.5%, p = 0.3328). In non-metastatic patients, compared to patients with positive apical MUC5AC expression, no expression (0%) was associated with worse overall survival (OS) (43 vs 13 m, p = 0.0322). In metastatic PDAC, there was no difference in OS between patients with positive or no apical MUC5AC expression (18 vs 21 m, p = 0.781). Compared to patients with positive cytoplasmic MUC5AC expression, patients with no cytoplasmic MUC5AC expression (0%) had no difference in OS in both non-metastatic (40 vs 32 m, p = 0.986) and metastatic (36 vs 12.5 m, p = 0.487) patients. Conclusions: MUC5AC expression assessment using IHC is feasible in patients with PDAC. In our cohort, apical, but not cytoplasmic, MUC5AC expression was different between metastatic and non-metatstaic patients and showed prognostic significance in non-metastatic patients. To our knowledge, this is the first study to show prognostic significance of MUC5AC expression in patients with PDAC using IHC.
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Khushman, Moh'd M., Arun Bhardwaj, Girijesh K. Patel, Javier Laurini, Kelly Roveda, Robert Donnell, Kelley Sherling, et al. "The prognostic significance of exosomal marker (CD63) expression using immunohistochemistry (IHC) in patients with pancreatic ductal adenocarcinoma (PDAC)." Journal of Clinical Oncology 35, no. 15_suppl (May 20, 2017): e15730-e15730. http://dx.doi.org/10.1200/jco.2017.35.15_suppl.e15730.
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e15730 Background: Exosomes are important mediators of intercellular communication, and play pivotal roles in cancer progression, metastasis and chemoresistance. Exosomal membranes are enriched in endosomes-specific tetraspanins (CD63 and CD9). In patients with PDAC, positive correlation between CD9 expression and overall survival (OS) was reported. However, CD63 expression was conserved in all patients without reported prognostic significance. Here, we explored the prognostic significance of CD63 expression using IHC in patients with PDAC of mixed gender and racial background. Methods: Between 2012 and 2016, 49 patients with PDAC treated at Mitchell Cancer Institute had available tissue (pancreatic resected tissue/biopsy [N = 29] or metastatic site biopsy liver, omentum or bone (N = 20)) for CD63 staining using IHC. Two pathologists independently scored the expression of CD63. Staining intensity was graded from 1-3. Staining percentage was estimated in 10% increments. Mean Quick-score (Intensity X Percentage of staining) was calculated. Unpaired t test was used for statistical analysis. Results: Median age was 64 years (range 42-85). 53% are males. 67% white, 27% African Americans (AA) and 6% are other ethnicities. 41% had stage IV disease while 49% had stage I, II and III. Tumor involved the head (51%), body (20%) and tail (29%). The mean CD63 Q score is slightly higher in AA compared to white (157 vs 149, P = 0.76). The mean CD63 Q score is higher in the pancreatic tissues compared to metastatic sites tissues (185 Vs 102, P = 0.0002). In our cohort, patients with mean CD63 Q score > = 140 had longer median OS compared to patients with mean Q score of < 140 (19 months Vs 3 months, P = 0.0003) and progression free survival (PFS) (12 months vs 1 month, P = 0.0043). Conclusions: In our cohort of patients with PDAC, there was no racial difference in CD63 expression between white and AA. The expression of CD63 is higher in the pancreas compared to metastatic sites (liver, omentum and bone). There is positive correlation between CD63 expression and PFS and OS. To our knowledge, this is the first study to show prognostic significance of CD63 expression in patients with PDAC using IHC.
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Poynter, Jenny N., Michaela Richardson, Erica Langer, Anthony Hooten, Michelle A. Roesler, Betsy A. Hirsch, Phuong L. Nguyen, Adina Cioc, Erica Warlick, and Julie A. Ross. "Association Between Mitochondrial DNA Haplogroup and Myelodysplastic Syndromes." Blood 126, no. 23 (December 3, 2015): 2885. http://dx.doi.org/10.1182/blood.v126.23.2885.2885.
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Abstract Background Polymorphisms in mitochondrial DNA can be used to group individuals into haplogroups that reflect human global migration. These mitochondrial variants are associated with differences in mitochondrial function and have been associated with multiple diseases, including cancer. In this analysis, we evaluated the association between mtDNA haplogroup and risk of myelodysplastic syndromes (MDS). Methods Cases were identified by rapid case ascertainment through the population-based Minnesota Cancer Surveillance System (MCSS). Participants were recruited to the MDS study if they were diagnosed with MDS between April 1, 2010 and October 31, 2014. Eligibility criteria included residence in Minnesota, age at diagnosis between 20 and 85 years, and ability to understand English or Spanish. Centralized pathology and cytogenetics review were conducted to confirm diagnosis and classify by subtypes. Controls were identified through the Minnesota State driver's license/identification card list. Genomic DNA from cases and controls was collected using Oragene DNA collection kits (DNA Genotek, Ontario, Canada) and extracted via Autopure LS Instrument according to manufacturer's instructions (Qiagen). We genotyped 15 mtSNPs that capture common European mitochondrial haplogroup variation (Mitchell et al Hum Genet 2014; Raby et al J Allergy Clin Immunol 2007) on the Sequenom iPLEX Gold MassArray platform (Sequenom, Inc., San Diego, CA) in the University of Minnesota Genomics Core. Because haplogroup frequencies vary by race and ethnicity, we restricted analyses to non-Hispanic white cases and controls. All statistical analyses were conducted using SAS v.9.3 (SAS Institute, Cary, NC). Odds ratios (OR) and 95% confidence intervals (CI) were calculated. We also evaluated associations by MDS subtype and IPSS-R risk category. Results We were able to classify 215 cases with confirmed MDS and 522 controls into one of the 11 common European haplogroups. The distribution of haplogroups in our control sample was similar to the distribution reported in a previous sample of non-Hispanic white individuals from the United States (Mitchell et al Hum Genet 2014), with the highest number in the H haplogroup (42%). Due to small sample sizes in some subgroups, we combined mt haplogroups into larger bins based on the haplogroup evolutionary tree, including HV (H+V), JT (J+T), IWX (I+W+X), UK (U+K), and Z (van Oven & Kayser Hum Mut 2009) for comparisons of cases and controls. Using haplogroup HV as the reference group, we found a statistically significant association between haplogroup JT and MDS (OR=0.57, 95% CI 0.36, 0.90, p=0.02). No other significant associations were observed in a comparison of cases and controls (Figure). In the analysis stratified by MDS subtype, the association with haplogroup JT reached statistical significance only in MDS cases with the RCMD subtype (OR=0.42, 95% CI 0.18, 0.97), although the association was similar in magnitude for RARS and the p-value for heterogeneity was non-significant (0.76). Similarly, the associations between haplogroup JT and MDS were similar in the analysis stratified by IPSS-R risk category (p-value for heterogeneity = 0.71). Conclusions In this population-based study of MDS, we observed an association between mtDNA haplogroup JT and risk of MDS. Previous studies using cybrid cells have reported functional differences by mtDNA haplogroup and provide biological plausibility for the observed association, including higher capacity to cope with oxidative stress in haplogroup T (Meuller et al PLoS One 2012) and lower levels of ATP and reactive oxygen species production in haplogroup J (Kenney et al PLoS One 2013). Further studies of the relationship between mtDNA variation and MDS are warranted in larger sample sizes. Figure 1. Association between mtDNA haplogroup and MDS Figure 1. Association between mtDNA haplogroup and MDS Disclosures No relevant conflicts of interest to declare.
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Saad, Mariam, Aik Choon Tan, Issam El Naqa, Sandra Lee, F. Stephen Hodi, Lisa Butterfield, William LaFramboise, et al. "88 Evidence of enhanced immune activation within the tumor microenvironment and the circulation of female patients with high-risk melanoma compared to males." Journal for ImmunoTherapy of Cancer 9, Suppl 2 (November 2021): A96. http://dx.doi.org/10.1136/jitc-2021-sitc2021.088.
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BackgroundSex differences in tumor immunity and response to immunotherapy were shown in murine models and descriptive analyses from recent clinical trials. We recently reported that female gender is a favorable prognostic marker for survival benefit following ipilimumab and high dose interferon-alfa (HDI) adjuvant therapy of high-risk melanoma in the ECOG-ACRIN E1609 trial (N=1670). Therefore, we investigated differences in candidate immune biomarkers in the circulation and tumor microenvironment (TME) of female and male patients.MethodsGene expression profiling (GEP) was performed on the tumor biopsies of 718 (454 male, 264 female) patients. The primary endpoint was mRNA expression profiling using U133A 2.0 Affymetrix gene chips. Raw microarray data sets were normalized by using the Robust Multi-array Average (RMA) method using Affymetrix Power Tools (APT) as previously published. Multiple probe sets representing the same genes were collapsed by using the probe with maximum gene expression. Gene set enrichment analysis (GSEA) was performed by comparing the female and male tumor samples, and gene sets with FDR q-value <0.1 were deemed as significant. Similarly, peripheral blood (serum and PBMC) samples were tested for soluble (Luminex) and cellular (multicolor flow cytometry) prognostic biomarkers in a subset of patients (N=321; 109 female and 212 male). All patients provided an IRB-approved written informed consent.ResultsAmong the subset of patients tested for circulating biomarkers, females were significantly younger than males (P=0.03). Testing PBMCs, the percentages of CD3+ T cells (P=0.04) and CD3+CD4+ helper T cells (P=0.0005) were significantly higher in female patients compared to males. Also, there were trends toward higher levels of proinflammatory cytokines IL1beta (P=0.07) and IL6 (P=0.06) in females. On the other hand, males had significantly higher percentages of monocytes (P=0.03). Further, there were trends toward higher percentages of CD3+/CD4+/CD25hi+/Foxp3+ (P=0.1) and CD3+/CD4+/CD25+/CD127low+ (P=0.1) T-reg in male patients compared to females. Among the cohort of patients (N=718) with tumor GEP data, females were significantly younger than males (P=0.0009). GEP identified pathways and genes related to immune cell infiltration and activation that were significantly enriched in the tumors of females compared to males (table 1).Abstract 88 Table 1Immune pathways significantly enriched in tumors of femalesConclusionsFemale gender was associated with adjuvant immunotherapeutic benefits and female patients were more likely to have evidence of immune activation within the TME and the circulation, supporting a potentially important role for female related factors in the immune response against melanoma, and these require further investigation.AcknowledgementsWe are grateful to the patients and family members who participated in the E1609 trial and the E1609 trial investigators. This study was conducted by the ECOG-ACRIN Cancer Research Group (Peter J. O’Dwyer, MD and Mitchell D. Schnall, MD, PhD, Group Co-Chairs) and supported by the National Cancer Institute of the National Institutes of Health under the following award numbers: U10CA180794, U10CA180820, U10CA180888, UG1CA233180, UG1CA233184. Biomarkers studies were supported under the following award number: P50CA12197310 (Tarhini and Kirkwood). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.Trial RegistrationNCT01274338Ethics ApprovalThe E1609 study protocol was approved by the institutional review board of each participating institution and conducted in accordance with Good Clinical Practice guidelines as defined by the International Conference on Harmonization. All patients provided an IRB-approved written informed consent.ConsentNot applicable.
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Tarhini, Ahmad, Aik Choon Tan, Issam El Naqa, Sandra Lee, F. Stephen Hodi, Lisa Butterfield, William LaFramboise, et al. "87 Enhanced immunogenicity within the tumor microenvironment and the circulation of high-risk melanoma patients with unknown primary compared to those whose primary melanoma is known." Journal for ImmunoTherapy of Cancer 9, Suppl 2 (November 2021): A95. http://dx.doi.org/10.1136/jitc-2021-sitc2021.087.
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BackgroundWe recently reported data supporting the unknown primary status as a potentially distinct prognostic group among high-risk melanoma patients treated with ipilimumab and high dose interferon-alfa (HDI) in the ECOG-ACRIN E1609 trial (N=1670) with improved RFS and OS outcomes compared to known primary. Therefore, we investigated differences in candidate immune biomarkers in the circulation and tumor microenvironment (TME) of patients with unknown compared to those with known primary melanoma enrolled in this trial that tested adjuvant ipilimumab at 3 and 10 mg/kg versus HDI.MethodsGene expression profiling (GEP) was performed on the tumor biopsies of 718 (102 unknown, 616 known primary) melanoma patients. The primary endpoint was mRNA expression profiling using U133A 2.0 Affymetrix gene chips. Raw microarray data sets were normalized by using the Robust Multi-array Average (RMA) method using Affymetrix Power Tools (APT) as previously published. Multiple probe sets representing the same genes were collapsed by using the probe with maximum gene expression. Gene set enrichment analysis (GSEA) was performed by comparing the unknown and known primary tumor samples, and gene sets with FDR q-value <0.1 were deemed as significant. Similarly, peripheral blood (serum and PBMC) samples were tested for soluble (Luminex) and cellular (multicolor flow cytometry) immune biomarkers in a subset of patients (N=321; 66 unknown and 255 known primary). All patients provided an IRB-approved written informed consent.ResultsUnknown primary melanoma cases represented 12.8% of the total E1609 study population (N=1670) including 11.7% on the ipilimumab arms and 14.7% on the HDI arm. Stratifying by stage, relapse free survival (RFS) (P=0.001) and overall survival (OS) (P=0.009) were significantly better for patients with unknown primary tumor compared to known primary. Including only ipilimumab-treated patients, RFS (P=0.005) and OS (P=0.023) were significantly better in favor of the unknown primary status. Among the cohort of patients with tumor GEP data (N=718), GEP identified pathways and genes related to autoimmunity, inflammation, immune cell infiltration and immune activation that were significantly enriched in the unknown primary tumors compared to known primaries (table 1). Among the subset of patients tested for circulating biomarkers, patients with unknown primary melanoma had significantly higher circulating levels of IL-2R than those with known primary (P=0.04).Abstract 87 Table 1Immune pathways enriched in unknown primary melanomaConclusionsUnknown primary high-risk melanoma patients had significantly better prognosis and evidence of significantly enhanced immune activation within the TME and the circulation, supporting the designation of unknown primary melanoma as a distinct prognostic marker in patients with high-risk melanoma.AcknowledgementsWe are grateful to the patients and family members who participated in the E1609 trial and the E1609 trial investigators. This study was conducted by the ECOG-ACRIN Cancer Research Group (Peter J. O’Dwyer, MD and Mitchell D. Schnall, MD, PhD, Group Co-Chairs) and supported by the National Cancer Institute of the National Institutes of Health under the following award numbers: U10CA180794, U10CA180820, U10CA180888, UG1CA233180, UG1CA233184. Biomarkers studies were supported under the following award number: P50CA12197310 (Tarhini and Kirkwood). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.Trial RegistrationNCT01274338Ethics ApprovalThe E1609 study protocol was approved by the institutional review board of each participating institution and conducted in accordance with Good Clinical Practice guidelines as defined by the International Conference on Harmonization. All patients provided an IRB-approved written informed consent.ConsentNot applicable.
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Vapiwala, Neha, Yu-Hui Chen, Steve Y. Cho, Fenghai Duan, Christos Kyriakopoulos, Daniel H. Shevrin, Rana R. McKay, et al. "PET-directed local or systemic therapy intensification in prostate cancer patients with post-prostatectomy biochemical recurrence: A trial of the ECOG-ACRIN Cancer Research Group (EA8191)." Journal of Clinical Oncology 39, no. 6_suppl (February 20, 2021): TPS267. http://dx.doi.org/10.1200/jco.2021.39.6_suppl.tps267.
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TPS267 Background: Radiation therapy (RT) to the prostate bed and pelvic nodes with short-term androgen deprivation therapy (STAD) is considered a standard of care (SOC) salvage therapy (ST) paradigm for prostate cancer (PC) patients (pts) with post-prostatectomy (RP) biochemical recurrence (BCR). Fluciclovine-PET/CT imaging is FDA-approved in this setting, with improved accuracy for detection of metastases (mets) not identified with conventional imaging (CIM). Given greater sensitivity and specificity of PET, its findings are being increasingly but variably applied to justify modification or omission of SOC therapies without high-level evidence of clinical benefit. PET may help identify candidates for local or systemic treatment intensification of otherwise non-tailored SOC. Earlier detection of mets with molecular imaging has led to increasing use of focally ablative met-directed RT, to delay or enhance systemic therapy through better local control. There is also interest in earlier use of advanced systemic therapy; apalutamide (Apa) is a nonsteroidal antiandrogen with established efficacy in improving overall and radiographic progression-free survival (PFS) for non-metastatic castrate-resistant and metastatic castration-sensitive PC, and potential activity for low-volume mets. This study will evaluate whether pts with PET-detected lesions benefit from such local or systemic treatment intensification approaches. Methods: PC pts with post-RP BCR (PSA>0.5ng/mL; >0.2 if RP within 12 mos), and negative CIM who are candidates for SOC ST (RT to prostate bed and pelvic nodes + STAD) and undergo SOC baseline PET are eligible. The study will initially use 18F-fluciclovine but permit additional radiotracers based on FDA approval and availability. Based on institutional clinical interpretation of the SOC PET, pts will be placed in Cohort 1 (PET-negative) or 2 (PET-positive for extra-pelvic mets). Cohort 1 will be randomized to SOC ST +/- Apa for 6 months and Cohort 2 will be randomized to SOC ST and Apa +/- met-directed RT to PET-positive lesions. The primary endpoint is PFS, defined as time from randomization to radiographic progression on CIM, symptomatic disease or death. Primary objectives are to evaluate whether addition of Apa to SOC ST and addition of met-directed RT to SOC ST and Apa could prolong PFS in Cohorts 1 and 2, respectively. For Cohort 1, 480 pts will be randomized with 85% power to distinguish 5-year PFS rate of 90% (Apa arm) vs. 80% (SOC arm) using one-sided stratified logrank test with type I error of 0.025. For Cohort 2, 324 pts will be randomized with 85% power to distinguish 5-year PFS rate of 76.5% in experimental arm from 61.5% in control arm. Secondary endpoints include overall and event-free survival, toxicity, and PET progression. Trial was activated on October 8, 2020; NCT04423211. Acknowledgement: This study was conducted by the ECOG-ACRIN Cancer Research Group (Peter J. O'Dwyer, MD and Mitchell D. Schnall, MD, PhD, Group Co-Chairs) and supported by the National Cancer Institute of the National Institutes of Health under the following award numbers: U10CA180794, U10CA180820, U10CA180868, U10CA180888, U10CA180821, UG1CA233196, UG1CA233253, UG1CA233277, UG1CA233328, and UG1CA233330. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. Mention of trade names, commercial products, or organizations does not imply endorsement by the U.S. government. Clinical trial information: NCT 04423211.
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Coates, Peter A. "Robert D. Mitchell and Milton B. Newton, The Appalachian Frontier: Views from the East and the Southwest (London: Historical Geography Research Group, Institute of British Geographers. Historical Geography Research Series Publication No. 21, 071988, £4.95). Pp. 64. ISBN I 870074 033." Journal of American Studies 24, no. 3 (December 1990): 426. http://dx.doi.org/10.1017/s0021875800033788.
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Ganzel, Chezi, Larry D. Cripe, Zhouxin Sun, Hugo F. Fernandez, Peter A. Cassileth, Dan Douer, Jacob M. Rowe, et al. "Very Poor Long-Term Survival, Also in Contemporary Studies, of Patients with AML Who Relapse after Achieving a First Complete Remission: The ECOG-ACRIN Cancer Research Group Experience." Blood 126, no. 23 (December 3, 2015): 1315. http://dx.doi.org/10.1182/blood.v126.23.1315.1315.
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Abstract This study was coordinated by the ECOG-ACRIN Cancer Research Group (Robert L. Comis, MD and Mitchell D. Schnall, MD, PhD, Group Co-Chairs) and supported in part by Public Health Service Grants CA180794, CA180820, CA180795, CA180791, CA189859, CA180790, CA180853, and from the National Cancer Institute, National Institutes of Health and the Department of Health and Human Services. Its content is solely the responsibility of the authors and does not necessarily represent the official views of the National Cancer Institute. Background: Relapse after achieving a complete remission (CR) in AML portends for a poor prognosis and allogeneic transplant after achieving a second remission is the only chance for cure. Patients who undergo a transplant have a 30-40% chance of long term survival. This is a follow-up of a report published 10 years ago (Rowe JM, ASH 2005, abstract 546) and includes contemporary studies and longer follow-up. The study examines the long term overall survival (OS) of AML patients who relapsed after achieving first CR in 9 successive ECOG-ACRIN trials for newly-diagnosed AML patients (E3483, E3489, PC486, E3993, E4995, E1490, E3997, E1900 and E3999) from March 1984 to November 2008. Methods: OS was defined as time from first relapse to death from any cause. Kaplan-Meier estimates were used to estimate the event-time distributions for OS. Multivariate model stratified on protocol and treatment were used to examine whether the following factors are prognostic for OS from relapse: age, gender, cytogenetic risk, ECOG performance status, WBC, platelets, hemoglobin, marrow blasts, peripheral blasts, and duration of CR. All P values were based on 2-sided tests. Results: A total of 3160 patients were enrolled in the 9 studies. The median follow-up on patients still alive was 10.0 years. Among those 3160 patients enrolled, 1864 (58.9%) achieved first CR of which 1086 (58.2%) had documented relapse. The median age at diagnosis of the relapsed patients was 50 (range: 16-84) and 50.6% were males. Fifty percent of the patients had reliable cytogenetic results. Of those, 13.5% had favorable cytogenetics, 55.8% - intermediate and 30.6% had unfavorable baseline results. The median OS from relapse was 0.5 years. The 2- and 5-year OS were 16(±1)% and 10(±1)%, respectively. This is true in even the most contemporary studies (E1900 and E3999) with median OS of 0.6 and 0.4 years, respectively. By age stratification (< or ≥ 55), 5-year OS was 13(±1)% and 5(±1)%, respectively (figure 1). Among patients<55, those with unfavorable cytogenetics had the poorest prognosis (median OS of 0.4 years and 5-year OS of 6(±3)%. Those with favorable and intermediate cytogenetics had similar OS with 0.7 and 0.6 years median OS and 5-year OS of 16(±5)% and 17(±3)%, respectively (figure 2). Multivariate analysis was perfomed on 517 patients who had enough baseline information, including cytogenetics. Factors that were significantly associated with OS from relapse included: age (p<0.001), ECOG performance status (p=0.04), hemoglobin (p=0.03), cytogenetics (p=0.045) at baseline and duration of CR (p<0.001). Conclusions: The short- and long-term OS of AML patients post-relapse is dismal (<10%). Although age<55 and favorable cytogenetics at diagnosis are relatively good prognostic factors, the general survival of even these patients is very poor. Disappointingly, these data are also applicable to the most contemporary studies. Long-term survival was possible only in the minority of patients who survived the relapse, achieved a second CR and then successfully underwent an allogeneic transplant. These data are crucial when considering post-remission strategy, and suggest that offering a therapy most likely to lead to cure in CR1 is the preferred option. Figure 1. Probability of OS from relapse by age group Figure 1. Probability of OS from relapse by age group Figure 2. Probability of OS from relapse by cytogenetic risk for patients age <55 Figure 2. Probability of OS from relapse by cytogenetic risk for patients age <55 Disclosures Douer: Gilead: Consultancy. Rowe:BioSight Ltd.: Consultancy, Membership on an entity's Board of Directors or advisory committees; BioLineRx Ltd.: Consultancy; Amgen: Consultancy.
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McLellan, Linda, Brad Pohlman, Lisa Rybicki, Larry Foster, Shawnda Tench, Michele Cooper, Millie McKenzie, et al. "Distress Screening Scores of Malignant and Benign Hematology Patients: Results of a Pilot Project." Blood 120, no. 21 (November 16, 2012): 3173. http://dx.doi.org/10.1182/blood.v120.21.3173.3173.
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Abstract Abstract 3173 The Cleveland Clinic Taussig Cancer Institute completed a pilot project on distress screening as part of the plan to address the American College of Surgeons Commission on Cancer requirement (Standard 3.2: Psychosocial Distress Screening) to screen malignant and benign hematology patients for distress and psychosocial health needs. Over a two week period every hematology patient seeing a physician or mid-level provider completed the distress screening instrument Emotions Thermometer (ET), a five dimensional tool that includes four predictor domains: distress, anxiety, depression, anger and one outcome domain of need for help. Each domain is rated on a 0 to 10 Likert type scale, in a thermometer format. With respect to validity and reliability, the sensitivity and specificity of the ET tool has been found comparable to known validity and reliability of other accepted measures of distress, depression, and anxiety (Mitchell, et al, 2009). Per National Comprehensive Cancer Network (NCCN) guidelines, a score of 4 or higher on distress screening warrants a referral to a psychosocial professional. Distress scores 4 and over were compared among the diagnoses using the Chi-Square test. When the overall P-value was significant (P <0.05), at least two groups differed, and pairwise comparisons were conducted to determine which diagnostic groups differed. Of the five thermometer domains, patients scored highest on anxiety. There were no differences among diagnoses on anger (P=0.51), but there were differences in the other four domains (P<0.001 distress, depression, and need for help; P=0.026 anxiety). For all four, pairwise comparisons indicated that multiple myeloma patients had higher (worse) scores on anxiety, distress, depression, and need for help than all other diagnoses; there were no differences among benign hematology, leukemia/MDS/CML, or lymphoma/CLL. While this pilot project does not answer why multiple myeloma patients report levels of psychosocial distress significantly higher than other hematology patients, increased attention needs to be given to address these patients' experience of anxiety, depression, and distress. This project provides valuable information about the levels of distress experienced among all hematology patients and is useful for determining staffing levels of psychosocial professionals needed to address distress. Percentage of Emotion Thermometer Scores Over 4 Diagnosis Distress Anxiety Depression Anger Help Benign Hem 18% 27% 18% 12% 7% Leuk/MDS/CML 19% 28% 17% 9% 14% Lymph/CLL 18% 31% 16% 14% 13% Myeloma 38% 44% 35% 15% 27% P-value <0.001 0.026 <0.001 0.51 <0.001 Disclosures: No relevant conflicts of interest to declare.
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Mateos, Marion K., Toby N. Trahair, Chelsea Mayoh, Pasquale M. Barbaro, Rosemary Sutton, Tamas Revesz, Draga Barbaric, et al. "Clinical Predictors of Venous Thromboembolism during Therapy for Childhood Acute Lymphoblastic Leukemia." Blood 128, no. 22 (December 2, 2016): 1182. http://dx.doi.org/10.1182/blood.v128.22.1182.1182.
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Abstract Venous thromboembolism (VTE) is an unpredictable and life-threatening toxicity that occurs early in acute lymphoblastic leukemia (ALL) therapy. The incidence is approximately 5% in children diagnosed with ALL [Caruso et al. Blood. 2006;108(7):2216-22], which is higher than in other pediatric cancer types [Athale et al. Pediatric Blood & Cancer. 2008;51(6):792-7]. Clinical risk factors for VTE in children during ALL therapy include older age and the use of asparaginase. We hypothesized that there may be additional risk factors that can modify VTE risk, beyond those previously reported [Mitchell et al. Blood. 2010;115(24):4999-5004]. We sought to define early predictive clinical factors that could select a group of children at highest risk of VTE, with possible utility in an interventional trial of prophylactic anticoagulation. We conducted a retrospective study of 1021 Australian children, aged 1-18 years, treated between 1998-2013 on successive BFM-based ALL therapies. Patient records were reviewed to ascertain incidence of VTE; and to systematically document clinical variables present at diagnosis and during induction/consolidation phases of therapy. The CTCAE v4.03 system was used for grading of VTE events. Multivariate logistic and cox regression were used to determine significant clinical risk factors associated with VTE (SPSS v23.0). All P values were 2-tailed, significance level <.05. The incidence of on-treatment VTE was 5.09% [96% ≥Grade 2 (CTCAE v4.0)]. Age ≥10 years [P =.048, HR 1.96 (95% confidence interval= 1.01-3.82)], positive blood culture in induction/consolidation [ P =.009, HR 2.35 (1.24-4.46)], extreme weight at diagnosis <5th or >95th centile [ P =.028, HR 2.14 (1.09-4.20)] and elevated peak gamma-glutamyl transferase (GGT) >5 x upper limit normal in induction/consolidation [ P =.018, HR 2.24 (1.15-4.36)] were significantly associated with VTE in multivariate cox regression modeling. The cumulative incidence of VTE, if all 4 clinical risk factors in our model were present, was 33.33%, which is significantly greater than the incidence of VTE for a patient without any risk factors (1.62%, P <.001). These 4 clinical factors could be used as a basis for assigning thromboprophylaxis in children with ALL. Our model detected 80% (42/52) of all VTE events by incorporating one or more risk factors. An equal proportion of patients eventually developing VTE could be predicted by weight and age ≥10 years; or later bacteremia and elevated GGT. Bacteremia, when present as a risk factor, preceded VTE in 80% of cases (20/25 cases) at a median of 29 days before VTE (range 3-668 days). The negative predictive value (NPV), specificity and sensitivity for the 4 risk factor model were 98.38%, 98.70% and 28.57% respectively. If 3 specified risk factors were included in the algorithm, such as 2 baseline and one treatment-related variable, the incidence of VTE was ≥25%, NPV 98.38%, specificity ≥96.19% and sensitivity 80%. The high NPV and high specificity mean the model can successfully exclude children who are not at increased risk of VTE. The challenge is to balance unnecessary exposure to anticoagulation against the risk of development of VTE. We have identified novel clinical risk factors in induction/consolidation - positive blood culture, hepatic enzymatic elevation and extreme weight at diagnosis- that may highlight risk mechanisms related to VTE pathogenesis. Our predictive model can define a group at highest risk of VTE who may benefit from randomized trials of prophylactic anticoagulation in childhood ALL therapy. Acknowledgments: The authors acknowledge support from the Kids Cancer Alliance (a Translational Cancer Research Centre of Cancer Institute NSW), Cancer Institute New South Wales, Royal Australasian College of Physicians - Kids Cancer Project Research Entry Scholarship, Cancer Therapeutics CRC (CTx) PhD Clinician Research Top-Up Scholarship, The Kids Cancer Project, Australian and New Zealand Children's Haematology Oncology Group, ASSET study members, data managers and clinical research associates at each site. Disclosures No relevant conflicts of interest to declare.
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Ganzel, Chezi, Wang Xin Victoria, Adele K. Fielding, Jacob M. Rowe, Susan M. Richards, Georgina Buck, Rajesh Chopra, et al. "in Philadelphia-Chromosome-Negative Acute Lymphoblastic Leukemia, Late Relapses Are Not Uncommon, Occur Mostly in Patients at Standard Risk and Have a Relatively Favorable Outcome. Results of the International ALL Trial: MRC Ukallxii/ECOG E2993." Blood 126, no. 23 (December 3, 2015): 795. http://dx.doi.org/10.1182/blood.v126.23.795.795.
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Abstract This study was coordinated by the ECOG-ACRIN Cancer Research Group (Robert L. Comis, MD and Mitchell D. Schnall, MD, PhD, Group Co-Chairs) and the Medical Research Counsel, United Kingdom, and supported in part by Public Health Service Grants CA180820, CA180794, CA180790, CA189859, CA180853, CA180791, and from the National Cancer Institute, National Institutes of Health and the Department of Health and Human Services. Its content is solely the responsibility of the authors and does not necessarily represent the official views of the National Cancer Institute. Background: Late relapse in acute leukemia is considered a relatively rare event. Patients with acute myeloid leukemia (AML) are often considered cured of the disease at 3 years, but information regarding adult acute lymphoblastic leukemia (ALL) patients is scarce. Data are presented from one of the largest prospective adult ALL studies, the MRC UKALLXII/ECOG E2993, to evaluate the rate and characteristics of late relapse in ALL. For this purpose, late relapse was defined, arbitrarily, as relapse 3 years post achievement of complete remission (CR) and very late relapse was defined as relapse > 5 years from CR. Methods: The UKALLXII/ECOG E2993 was an international ALL trial conducted jointly by the MRC in the United Kingdom and ECOG in the United States. All patients received identical induction therapy, followed by central nervous system prophylaxis. Patients with a sibling donor (or a matched unrelated donor in Philadelophia-chromosome-positive ALL) were assigned to receive an allogeneic hematopoietic stem cell transplant (HSCT); all others were randomized to undergo an autologous transplant or protracted standard consolidation/ maintenance therapy. The study accrued 2109 patients from 1993 to 2008. Following relapse, patients were followed for survival. For this report only patients registered before the tyrosine kinase inhibitors era are included in the analysis. Results: 1518 study patients were eligible for this analysis, 1208 (79.6%) Philadelphia-chromosome negative (Ph-neg) and 267 (17.5%) Philadelphia-chromosome positive (Ph-pos). 1381 (91%) of the patients achieved CR; 93% of the Ph-neg and 82% of the Ph-pos. 572 patients (37.7%) underwent allogeneic HSCT. The median duration of follow-up of patients who achieved CR was 10 years. Among the 1381 patients who achieved CR, 626 (45.3%) had a documented relapse; 566 (90.4%) relapsed within 3 years of CR and 60 (9.6%) relapsed beyond 3 years ('late relapse') (Figure 1). Among these 60 patients, 18(2.9%) relapsed after 5 years ('very late relapse'). Table. Patients n CR All relapses Relapses< 3 years Relapses≥ 3 years Relapses≥ 5 years All patients 1518 1381 (91%) 626 (45.3%) 566 (90.4%) 60 (9.6%) 18 (2.9%) Ph-neg 1208 (79.6%) 1123 (93%) 485 (40.1%) 429 (88.5%) 56 (11.5%) 17 (3.5%) Ph-pos 268 (17.5%) 219 (82%) 124 (56.6%) 122 (98.4%) 2 (1.6%) 1 (0.8%) Relapse beyond 3 years occurred in 4.3% of all who achieved CR, in 5% of Ph-neg and 0.01% of Ph-pos patients. Among the 60 late relapses, the median time to relapse was 46 months. 61.7% of the late-relapse patients were males, median age was 32 years, 88.3% were B-lineage ALL and the median white cell count at diagnosis was 6000/ul. 56.7% were in cytogenetic standard risk, 8.3% at high risk and the data of 35% are unknown. The median survival for the late relapse patients was longer than for those who relapsed within 3 years. The overall survival (OS) of the 56 Ph-neg patients who relapsed beyond 3 years is shown in Fig 2. Table.Relapse > 3 yearsRelapse > 3 yearsMedian survival from relapse (months)5.411.23-year OS from relapse6.5%29%5-year OS from relapse5.6%19% Conclusions: Late relapses in adults with Ph-neg ALL are not uncommon. About 10% of relapses occur beyond 3 years and 4.3% of all ALL patients who achieved a CR can expect to have a late relapse. These data are in contrast to AML where only 1% of patients relapse beyond 3 years (Watts JM et al, 2014). Most of the late relapse patients were at standard risk and appeared to have a relatively favorable outcome post relapse. Patients with ALL, particularly those who are Ph-neg, cannot be considered as cured at 3 years and need to be closely followed. Figure 1. Time to relapse of Ph-pos and Ph-neg ALL Figure 1. Time to relapse of Ph-pos and Ph-neg ALL Figure 2. Survival from relapse for Ph-neg patients who relapsed after 3 years from CR. Figure 2. Survival from relapse for Ph-neg patients who relapsed after 3 years from CR. Disclosures Rowe: Amgen: Consultancy; BioSight Ltd.: Consultancy, Membership on an entity's Board of Directors or advisory committees; BioLineRx Ltd.: Consultancy. Douer:Gilead: Consultancy.
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Cortez, Antônio Carlos Leal. "Atividade física: da saúde a performance." Revista Brasileira de Fisiologia do Exercício 17, no. 3 (October 20, 2018): 138. http://dx.doi.org/10.33233/rbfe.v17i3.2577.
Повний текст джерелаАнотація:
É notório que a prática regular da atividade física, de forma geral, proporciona vários benefícios à saúde e ainda constitui uma forma efetiva como prevenção de doenças e na promoção da saúde. Todavia, estudos epidemiológicos, Shibata et al. [1] e HHS [2], apontam que o século XXI está sendo marcado pelo crescimento progressivo da inatividade física, tanto em países desenvolvidos como em países em desenvolvimento, como é o caso do Brasil.Segundo evidências científicas do American College of Sports Medicine (ACSM) [3], ACSM [4], Pitanga & Lessa [5], níveis de atividade física abaixo do estabelecido, de acordo com as diretrizes internacionais vigentes ACSM [6], Advisory Committee on International Physical Activity Questionnaire [7], Institute of Medicine [8], Organização Mundial da Saúde (OMS) [9] e União Europeia [10], estão associadas à incidência de doenças relacionadas com o estilo de vida como síndrome metabólica, doenças crônicas não-transmissíveis (DCNT), marcadores inflamatórios e câncer.Ressalta-se que a preocupação com o nível de atividade física vem desde a década de 1950, seja nos esportes de rendimento (voltados para a obtenção de resultados de aptidão física) bem como seus benefícios a saúde geral do indivíduo [2]. Entretanto, estudos como os de Mitchell et al. [11], Brawner, Churilla Júnior, Keteyian [12], Ferreira et al. [13] apontam que ainda é observado uma alta prevalência de inatividade física, entre diferentes populações no Brasil e no mundo, mesmo com a prática regular de atividade física apontada como um fator primordial na promoção da saúde e prevenção de algumas patologias [14-17].Dentro desse contexto, faz-se importante diferenciar conceitualmente atividade física de exercício físico. Segundo Nahas [18], atividade física é todo movimento corporal que leva a contração de músculos estriados esqueléticos, levando o corpo a gastos energéticos acima dos níveis de repouso. Por sua vez, exercício físico é todo e qualquer movimento corporal, que mantém ou melhora a aptidão física, capacidade funcional e/ou outros componentes relacionados às valências físicas, como melhora na composição corporal, aumento da flexibilidade, aperfeiçoamento das habilidades atléticas, aumento da capacidade cardiorrespiratória, além de benefícios psicossociais como aumento da autoestima, aceitação social e sensação de bem-estar [19-21].Entretanto, faz-se importante ressaltar que os objetivos planejados dentro de um programa de atividades físicas e/ou exercícios físicos sejam alcançados com a máxima eficiência e eficácia. Recomenda-se que todo processo desde avaliação, prescrição e acompanhamento sejam realizados por um profissional de Educação Física qualificado, devidamente credenciado ao Conselho – CREF/CONFEF. Dessa forma, estudos relacionados aos benefícios da intervenção de atividades e exercícios físicos orientados são de grande relevância, além de que tal temática não se esgota no mundo contemporâneo, em virtude do seu estado dinâmico [22].
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Nebbiosi, Gianni. "Psicoanalisi e istituti psicoanalitici indipendenti." INTERAZIONI, no. 2 (December 2009): 11–15. http://dx.doi.org/10.3280/int2008-002002.
Повний текст джерелаАнотація:
- The author makes a synthesis of some important theoretical-clinical models that have emerged over the last thirty years in North America. We are speaking about self psychology (Kohut), self theory and motivational system theory (Lichtenberg), intersubjective systems theory (Stolorow, Atwood, D. Orange), relational psychoanalysis (Mitchell) and intersubjectivity (Benjamin). The prominent characteristic of these models is to have created indipendent training psychoanalytic institutes. Nebbiosi's paper is a precious because it offers a completely different viewpoint from the European one that we can appreciate above all from the context of the "Psychoanalytic Geography" that the author presents.
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Jones, Kathryn Pritchard, Paul E. Grundy, and Max J. Coppes. "Recent Advances in the Genetics of Childhood Renal Cancers: A report of the 3rd International Conference on the molecular and clinical genetics of childhood renal tumors, together with the Mitchell Ross Symposium on anaplastic and other high risk embryonal tumors of childhood, 8-10th April 1999, Wistar Institute, Philadelphia, PA." Medical and Pediatric Oncology 35, no. 2 (2000): 126–30. http://dx.doi.org/10.1002/1096-911x(200008)35:2<126::aid-mpo8>3.0.co;2-4.
Повний текст джерела
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Kanakry, Jennifer A., Fangxin Hong, Otoniel Martinez-Maza, Sandra J. Horning, Leo I. Gordon, Randy D. Gascoyne, Lan L. Gellert, et al. "Serum Biomarkers Predict Outcomes in Advanced Hodgkin Lymphoma Independent of International Prognostic Score (IPS) and Treatment: Correlative Analysis from a Large North American Cooperative Group Trial." Blood 128, no. 22 (December 2, 2016): 2992. http://dx.doi.org/10.1182/blood.v128.22.2992.2992.
Повний текст джерелаАнотація:
Abstract Introduction: Progress in the treatment of patients with classical Hodgkin lymphoma (cHL) depends on identifying methods to better risk-stratify patients and assess prognosis and treatment response. While prognostic scores based on clinical characteristics have utility, inflammatory markers and signaling proteins may better reflect tumor biology, the microenvironment, or host response and might serve as prognostic factors. Increased expression of tumor-associated macrophage markers in tumor tissue, such as CD68 or CD163, has been shown to be associated with inferior survival outcomes in cHL patients. Blood-based markers are more practical in that specimens are readily and serially obtainable. Such markers, if shown to track with tumor response and/or prognosticate outcomes, can be used throughout treatment and follow-up. Some soluble markers, such as TARC (chemokine (C-C motif) ligand (CCL)-17) and soluble CD163 (sCD163), have been shown to reflect tumor burden and active disease, and markers such as soluble CD30 (sCD30), interleukin (IL)-6, chemokine (C-X-C motif) ligand (CXCL)-10/IP10, and IL-2 receptor have been associated with failure-free survival (FFS). Methods: Newly diagnosed cHL patients with locally extensive or advanced stage disease were prospectively enrolled in the Intergroup E2496 randomized controlled trial, which compared ABVD with Stanford V chemotherapy. A panel of serum cytokines, chemokines, and other soluble markers including TARC, CCL22, CCL24, sCD30, sCD163, CXCL10/IP10, CXCL13, soluble CD14 (sCD14), IL-6, IL-10, IL-12, and IL-13, IL1-receptor antagonist (IL1RA)) were measured in pretreatment serum specimens from 301 cHL patients (out of 854 on study) using multiplex (Luminex) bead array immunoassay (R&D Systems). Serum marker values were log-transformed for all analyses. Epstein-Barr virus (EBV) tumor status was determined by EBER in situ hybridization. A linear regression model was used to assess the association between pre-treatment serum marker levels and baseline clinical characteristics. A stratified Cox proportional hazards regression model was used to evaluate the association between serum marker levels as continuous variables and survival outcomes, including FFS (time from registration to disease progression/relapse or death) and overall survival (OS). Patients were divided into quartile groups based on serum marker levels and Kaplan-Meier curves were constructed with comparison using the stratified log-rank test. Three stratification factors were used in all modeling/testing include: stage I-II bulky vs. stage III-IV; IPS 0-2 vs 3-7; and treatment arms (Stanford V vs. ABVD). Two-sided p-values were reported. Results: Increased pre-treatment levels of CCL24, sCD30, sCD163, IP10, sCD14, IL-6, and IL-10 were associated with the presence of B symptoms, independent of age, tumor histology, and disease stage, in multivariate analysis. Higher sCD163 and IP10 levels were associated with EBV positive tumors and higher TARC, CCL22, and CXCL13 levels were associated with EBV negative tumors, after adjusting for age and histology. Several markers were associated with factors in the International Prognostic Score (Table 1). Adjusting for IPS, stage and treatment arms, high levels of IL1RA, sCD30, sCD163, IP10, and IL-10, were significantly (p<0.05) associated with inferior FFS. While high levels of TARC (p=0.02, hazard ratio (HR) 0.88, 95% confidence interval (CI) 0.79-0.98), and CXCL13 (p=0.04, HR 0.84, 95% CI 0.72-0.99) were associated with better OS, high levels of CD14 (p=0.02, HR 2.2, 95% CI 1.11-4.38), IP10 (p<0.0001, HR 2.22, 95% CI 1.64-3.00) and sCD163 (p=0.0002, HR 2.89, 95% CI 1.65-5.06) were associated with significantly inferior OS (Figure 1). Conclusion: These findings support prior work demonstrating the prognostic significance of markers such as CD163 in cHL tumor tissue with similar findings using a more readily available (blood-based) method of assessment. The study expands upon the number of blood-based markers shown to be prognostic in cHL, and associates high pre-treatment levels of several markers with IPS factors and other baseline clinical characteristics. Further, and most importantly, IP10 and sCD163 predict inferior FFS and OS independent of IPS and treatment. Disclosures Cheson: Pharmacyclics: Membership on an entity's Board of Directors or advisory committees, Research Funding; Gilead: Research Funding; Acerta: Membership on an entity's Board of Directors or advisory committees, Research Funding. Winter:Pharmacyclics: Research Funding; Medivation: Other: Provision of investigational agent for clinical trial; GSK: Research Funding; Seattle Genetics: Research Funding. Friedberg:Bayer: Honoraria, Other: Data Safety Monitoring Board. Kahl:This study was coordinated by the ECOG-ACRIN Cancer Research Group (Robert L. Comis, MD and Mitchell D. Schnall, MD, PhD, Group Co-Chairs) and supported by the National Cancer Institute of the National Institutes of Health under the following award number: Research Funding.
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Wilson, Wyndham H., Jung sin-Ho, Brandelyn Nicole Pitcher, Eric D. Hsi, Jonathan Friedberg, Bruce Cheson, Nancy L. Bartlett, et al. "Phase III Randomized Study of R-CHOP Versus DA-EPOCH-R and Molecular Analysis of Untreated Diffuse Large B-Cell Lymphoma: CALGB/Alliance 50303." Blood 128, no. 22 (December 2, 2016): 469. http://dx.doi.org/10.1182/blood.v128.22.469.469.
Повний текст джерелаАнотація:
Abstract Background: Diffuse large B-cell lymphoma (DLBCL) is comprised of multiple diseases with different outcomes, cell of origin and molecular pathogenesis. DLBCL derived from germinal center B-cells (GCB) and activated B-cells (ABC) constitutes over 80% of DLBCL. A small number of DLBCL tumors harbor MYC translocations, which are associated with a poorer prognosis. Primary mediastinal B-cell lymphoma (PMBL) occurs in younger patients and is typically treated with intensive or combined modality therapy. R-CHOP is the standard of care for DLBCL but has not been prospectively studied within DLBCL molecular subtypes. DA-EPOCH-R is an alternative and more dose-intensive regimen that showed a PFS of 81% at 4-years in a phase II multicenter CALGB study (Haematologica 2012; 97:758). CALGB/Alliance undertook a phase III randomized study to compare R-CHOP and DA-EPOCH-R in DLBCL and specifically within the GCB and ABC subtypes. Methods: Patients had stage II or higher newly diagnosed DLBCL, age ≥ 18 years and were HIV negative. Subjects were randomized 1:1 to receive R-CHOP or DA-EPOCH-R as previously published. Central nervous system prophylaxis in at-risk patients was 12 mg intrathecal methotrexate in cycles 3-6 (4 doses total). All subjects with accessible tumor were required to have a biopsy or waiver. Subjects received a total of 6 treatment cycles. The primary study endpoints were EFS of R-CHOP (Arm A) versus DA-EPOCH-R (Arm B) and to develop a molecular predictor of outcome based on GCB and ABC DLBCL. Additional analyses include toxicity, pharmacogenomics and analysis of tumor genetics by next generation sequencing, and. Results: 524 patients registered (262 on each arm) between May 2005 and May 2013. Efficacy analysis includes R-CHOP (n=233) and R-EPOCH (n=231) assigned patients with confirmed eligibility who received any treatment. Characteristics of patients registered to Arm A and B did not differ with median age (58; 56), male sex (53.2%; 53.7%), high-intermediate/high IPI (33.6%; 38.2%) and primary mediastinal B-cell lymphoma histology (6.9%; 5.2%). Therapy was completed per protocol in 89% and 83%, respectively, for Arm A and B, and disease progression on therapy was 2.6% and 1.7%. Adverse side effects leading to treatment discontinuation were 1.7% and 5.6%, respectively, for Arm A and B. Arm B compared to Arm A was associated with more grade 4 neutropenia (90%; 56%), grade 4 thrombocytopenia (35%; 6%), grade 3/4 febrile neutropenia (37%; 19%) and grade 3 neuropathy (motor: 8%;1% and sensory: 15%; 3%). Grade 5 events on study were the same in both arms. Preliminary analysis of EFS in confirmed eligible subjects shows no difference between Arm A and B with hazard ratio of 1.02 and p=0.89 at a median follow-up of 4.9 years. Overall survival is also similar with hazard ratio of 1.19 and p=0.40 at median 5.0 years. Additional analyses of EFS and OS by age (<60 and >=60) and by GCB versus ABC DLBCL are in process. Conclusions: There was no difference in EFS or OS between R-CHOP and DA-EPOCH-R when considering all patients. DA-EPOCH-R showed increased toxicity consistent with higher dose-intensity but not increased grade 5 toxicity. Compared to R-CHOP, more patients on DA-EPOCH-R did not complete treatment, which may reflect patterns of care or toxicity. Due to the clinical and genetic diversity of DLBCL, subset analyses are necessary to determine the effect of CNS relapse, GCB and ABC subtypes, age and IPI on outcomes of the two arms. These data do not address the efficacy of these regimens in PMBL or MYC+ DLBCL due to their low frequency, and where more dose-intense regimens appear to be important. Full molecular analyses are ongoing. Support: U10CA180821, U10CA180882, U10CA180888, CA180799, CA180820, CA180833, CA21076, CA21115.ClinicalTrials.gov Identifier: NCT00118209. Disclosures Hsi: Cellerant Therapeutics: Honoraria, Research Funding; Eli Lilly: Research Funding; Abbvie: Honoraria, Research Funding; Seattle Genetics: Honoraria, Speakers Bureau; HTG Molecular Diagnostics: Consultancy, Honoraria. Friedberg:Bayer: Honoraria, Other: Data Safety Monitoring Board. Cheson:Pharmacyclics: Membership on an entity's Board of Directors or advisory committees, Research Funding; Acerta: Membership on an entity's Board of Directors or advisory committees, Research Funding; Gilead: Research Funding. Bartlett:Gilead: Consultancy. Kahl:This study was coordinated by the ECOG-ACRIN Cancer Research Group (Robert L. Comis, MD and Mitchell D. Schnall, MD, PhD, Group Co-Chairs) and supported by the National Cancer Institute of the National Institutes of Health under the following award number: Research Funding. Zelenetz:Gilead Sciences: Research Funding.
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Kim, Jung-Hyun, Eun-Young Erin Ahn, Aliyeh Kennedy, Aaron Dinerman, and Thomas W. Butler. "Investigation of the Significance of Son Isoform mRNA Expression in Patients with Blood Cytopenias with/without Evidence of Myeloid Neoplasia." Blood 132, Supplement 1 (November 29, 2018): 5123. http://dx.doi.org/10.1182/blood-2018-99-120211.
Повний текст джерелаАнотація:
Abstract Myelodysplastic Syndrome (MDS) refers to hematopoietic neoplasms characterized by defective development of myeloid progenitors (erythrocytic, granulocytic, and megakaryocytic cell lines) and bone marrow. Clinical signs are characterized by blood cytopenias that can affect one or all three myeloid cell lines and bone marrow irregularities. Because of this heterogeneity, patients can present with anemia, thrombocytopenia, and/or neutropenia and it is important to determine prognosis, severity, and progression. Currently, the standard method for determining a diagnosis of MDS is based on metaphase cytogenetics which is limited in its scope. Other newer karyotyping procedures such a fluorescent in situ hybridization and single nucleotide polymorphism assay have improved the ability to evaluate patients. However, these tests still do not establish conclusive key fundamental biomolecular-genetic origins. It is hoped that in the future diagnostics will include information that further supports development of clinical prognostic and therapeutic options. Many mutational abnormalities have been discovered in MDS. The mutation of interest in this investigation is a shortened isoform of the SON protein which has been implicated to contribute to the pathogenesis of MDS, acute myelogenous leukemia (AML), and other malignancies. SON is a splicing cofactor that regulates the cell cycle and stability by interacting with genes and proteins known to contribute to tumorigenesis. Samples were obtained from patients being evaluated for cytopenia, MDS, AML, and other myeloid neoplasms and compared SON mRNA expression levels to control samples. Prior studies found that alternative splicing of the SON gene produces SON B and SON E both of which are truncated and aberrantly upregulated in patients with hematopoietic malignancies. The short SON isoforms antagonize the normal functions of full-length SON (SON F) leading to repression and splicing dysregulation of key cell cycle genes such as mixed lineage leukemia (MLL) family methyltransferases. SON regulates MLL complex-mediated histone methylation; this process requires the binding of menin, a tumor suppressor. The truncated SON isoform prevents this binding of meninto the MLL complex while opposing the transcription repressing function of full-length SON. A collaborative study between the laboratory of Dr. E.Y. Ahn and the hematology clinic of the Mitchell Cancer Institute further investigates the relationship between SON expression and hematopoietic disorders. SON E was found to be upregulated patients with anemias, MDS, and other myeloid neoplasms, a finding consistent with preceding research. Iron replete subjects and subjects taking erythropoietin did not follow his pattern. This new insight has yet to be explored due to limited data. In this study, samples were obtained from consented participants with cytopenias, MDS, or myeloproliferative disorders and analyzed for SON mRNA expression. Investigation revealed SON expression is abnormal in the majority of patients tested with cytopenias from either iron deficiency or myeloproliferative neoplasms or myelodysplastic syndrome. The differential expression of SON E appears to increase in patients with myeloproliferative neoplasms, myelodysplastic syndrome but differ in expression among patients. Deviations from the expected SON E short isoform expression were discovered for iron replete patients and a patient taking erythropoietin, leading to the conclusion that further clinical correlation of the SON expression in patients with iron deficiency and no MPD or MDS may further elucidate SON expression relevance in this disease and the relation to iron metabolism. In the future, longitudinal inspection of laboratory values and SON expression in patients with and without treatment is expected with specific emphasis on total body iron status as well as comparison to other mutational data (RUNX1 and GATA1). Overall, the results displayed potentiate SON isoform expression may be important in understanding the pathogenesis of malignant and non-malignant diseases of the blood. Disclosures No relevant conflicts of interest to declare.