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Lockwood, Kylee J., Katherine E. Harding, Jude N. Boyd, and Nicholas F. Taylor. "Predischarge home visits after hip fracture: a randomized controlled trial." Clinical Rehabilitation 33, no. 4 (January 14, 2019): 681–92. http://dx.doi.org/10.1177/0269215518823256.
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Objective: The objective of this study is to investigate whether home assessment visits prior to hospital discharge for patients recovering from hip fracture reduce falls and prevent hospital readmissions, within the first 30 days and six months after discharge home. Design: A randomized controlled trial was conducted. Setting: The study setting included hospital wards and the community. Participants: The study included adults 50 years and over recovering from hip fracture ( n = 77). Intervention: Both groups received inpatient rehabilitation and hospital-based discharge planning. In addition, the intervention group received a home assessment visit by an occupational therapist prior to discharge from hospital. Main measures: Primary outcomes were falls and hospital readmissions. Secondary outcome measures included Functional Independence Measure, Functional Autonomy Measurement Scale, Nottingham Extended Activities of Daily Living Scale, EuroQol five dimension scale questionnaire and Falls Efficacy Scale-International. Results: The intervention group had fewer hospital readmissions in the first 30 days compared to the control group (intervention n = 1, control n = 10; odds ratio (OR) 12.9, 95% confidence interval (CI) 1.5 to 99.2). The intervention group was observed to have fewer falls than controls in the 30 days after discharge (intervention n = 6, control n = 14; incidence rate ratio (IRR) = 0.41, 95% CI 0.15 to 1.11). Between-group differences favoured the intervention group for functional independence at six months (11.2 units, 95% CI 4.2 to 18.2). There were no other between-group differences. Conclusion: Home assessment visits by occupational therapists prior to hospital discharge for patients recovering from hip fracture reduced the number of readmissions to hospital, increased functional independence at six months and may have reduced the risk of falls in the first 30 days after discharge.
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Norman, John G., Stephen Brealey, Ada Keding, David Torgerson, and Amar Rangan. "Does time to surgery affect patient-reported outcome in proximal humeral fractures? A subanalysis of the PROFHER randomized clinical trial." Bone & Joint Journal 102-B, no. 1 (January 2020): 33–41. http://dx.doi.org/10.1302/0301-620x.102b1.bjj-2020-0546.r1.
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Aims The aim of this study was to explore whether time to surgery affects functional outcome in displaced proximal humeral fractures Methods A total of 250 patients presenting within three weeks of sustaining a displaced proximal humeral fracture involving the surgical neck were recruited at 32 acute NHS hospitals in the United Kingdom between September 2008 and April 2011. Of the 125 participants, 109 received surgery (fracture fixation or humeral head replacement) as per randomization. Data were included for 101 and 67 participants at six-month and five-year follow-up, respectively. Oxford Shoulder Scores (OSS) collected at six, 12, and 24 months and at three, four, and five years following randomization was plotted against time to surgery. Long-term recovery was explored by plotting six-month scores against five-year scores and agreement was illustrated with a Bland-Altman plot. Results The mean time from initial trauma to surgery was 10.5 days (1 to 33). Earlier surgical intervention did not improve OSS throughout follow-up, nor when stratified by participant age (< 65 years vs ≥ 65 years) and fracture severity (one- and two-part vs three- and four-part fractures). Participants managed later than reported international averages (three days in the United States and Germany, eight days in the United Kingdom) did not have worse outcomes. At five-year follow-up, 50 participants (76%) had the same or improved OSS compared with six months (six-month mean OSS 35.8 (SD 10.0); five-year mean OSS 40.1 (SD 9.1); r = 0.613). A Bland-Altman plot demonstrated a positive mean difference (3.3 OSS points (SD 7.92)) with wide 95% limits of agreement (-12.2 and 18.8 points). Conclusion Timing of surgery did not affect OSS at any stage of follow-up, irrespective of age or fracture type. Most participants had maximum functional outcome at six months that was maintained at five years. These findings may help guide providers of trauma services on surgical prioritization. Cite this article: Bone Joint J 2020;102-B(1):33–41
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Birlea, Marius, Sophie Penning, Kyle Callahan, and Jean Schoenen. "Efficacy and safety of external trigeminal neurostimulation in the prevention of chronic migraine: An open-label trial." Cephalalgia Reports 2 (January 1, 2019): 251581631985662. http://dx.doi.org/10.1177/2515816319856625.
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Objective: This trial explored the therapeutic utility and safety of external trigeminal neurostimulation (eTNS) as a preventive treatment in patients suffering from chronic migraine (CM). Methods: It was a monocenter, prospective, open-label, pilot trial conducted at the University of Colorado, Anschutz Medical Campus (Aurora, CO, USA). Participants were adult patients with a history of CM meeting International Classification of Headache Disorder-3 beta (2013) diagnostic criteria with or without medication overuse. After a 1-month baseline period, the patients still fulfilling the inclusion criteria applied at least one daily 20-min session of eTNS for 3 months. Primary outcomes were mean monthly changes in frequency of headache days and in overall acute headache medication intake. Results: Eighty patients were assessed for eligibility, 73 were included in the baseline period after which 58 entered the treatment period and were included in the intention-to-treat analysis. Compared to baseline, frequency of headache days decreased by −3.12 days (−16.21%, p < 0.001) and acute medication intake decreased from 26.33 to 18.22 (−30.81%, p < 0.001) during the third month of treatment. Twenty-six patients reported 47 minor adverse events, of which only 2 were related to the use of the device (skin irritation under the electrode and headache worsening with vertigo). Conclusions: This trial suggests that eTNS is safe and effective as prophylactic treatment for CM and indicates that a randomized sham-controlled trial is worthwhile. Trial registration: ClinicalTrials.gov (identifier: NCT02342743).
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Bolis, Giorgio, Giovanna Scarfone, Gianpiero Polverino, Francesco Raspagliesi, Saverio Tateo, Giovanni Richiardi, Mauro Melpignano, et al. "Paclitaxel 175 or 225 mg per Meters Squared With Carboplatin in Advanced Ovarian Cancer: A Randomized Trial." Journal of Clinical Oncology 22, no. 4 (February 15, 2004): 686–90. http://dx.doi.org/10.1200/jco.2004.03.017.
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Purpose To analyze the effect of different doses of paclitaxel with fixed doses of carboplatin in the treatment of ovarian cancer. Patients and Methods Patients with histologically confirmed epithelial ovarian cancer, International Federation of Gynecology and Obstetrics stages IIB to IV, were eligible for this randomized, multicenter study. Women were randomly assigned to treatment with (1) carboplatin at the dose (in milligrams) corresponding to the following formula: target area under the free carboplatin plasma concentration versus time curve (AUC) = 6 × (glomerular filtration rate + 25) mg/m2 (AUC6) plus paclitaxel 175 mg/m2 for six cycles every 21 days or (2) carboplatin AUC6 plus paclitaxel 225 mg/m2 for six cycles every 21 days. A total of 502 women entered the study. Results Pathologic complete response was documented in 132 patients (63.8%) in the 175 mg/m2 group and in 127 cases (55.7%) in the 225 mg/m2 group (χ2 P = .090). The 4-year progression-free survival rate was 41.5% (SE = 3.5) in the 175-mg group and 39.2% (SE = 3.5) in the 225-mg group. The corresponding 4-year survival rates were 46.2% (based on 115 deaths) and 47.3% (based on 113 deaths), respectively. Conclusion This randomized trial suggests that paclitaxel 175 mg/m2 plus carboplatin AUC6 is the schedule with a more favorable profile than paclitaxel 225 mg/m2 plus carboplatin AUC6.
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Conte, P. F., M. Bruzzone, S. Chiara, M. R. Sertoli, M. G. Daga, A. Rubagotti, A. Conio, M. Ruvolo, R. Rosso, and L. Santi. "A randomized trial comparing cisplatin plus cyclophosphamide versus cisplatin, doxorubicin, and cyclophosphamide in advanced ovarian cancer." Journal of Clinical Oncology 4, no. 6 (June 1986): 965–71. http://dx.doi.org/10.1200/jco.1986.4.6.965.
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After primary surgery, 125 patients with epithelial ovarian cancer (International Federation of Gynaecology and Obstetrics [FIGO] 1c + IIb + IIc = 22 patients, FIGO III = 82 patients, FIGO IV = 21 patients) were randomly allocated to receive PC (cisplatin 50 mg/m2 + cyclophosphamide 600 mg/m2 on day 1 every 28 days) (corrected) or PAC (PC + doxorubicin 45 mg/m2). After six cycles, patients clinically disease-free or with resectable residual disease were submitted to second-look surgery. After restaging, patients in surgical complete response (CR) stopped treatment while those responding partially (PR) received six more courses; patients whose disease progressed were excluded from the study. Among patients with measurable disease, the following clinical response rates were observed: PC = 20% CR, 34.3% PR, 14.3% stable disease, and 31.4% progression; PAC = 40.6% CR, 15.6% PR, 12.5% stable disease, and 31.3% progression. In the 75 patients submitted to second look, the results have been the following: PC = 39.5% CR, 36.8% PR, 7.9% stable disease, and 15.8% progression; PAC = 62.2% CR, 18.9% PR, 10.8% stable disease, and 8.1% progression. The difference in surgical complete response in favor of the PAC regimen is significant (P less than .05). Median survival and progression-free survival were 800 and 400 days, respectively, for PAC arm; median survival and progression-free survival were 680 and 380 days, respectively, for PC. These differences are not significant. Probability of survival was affected by FIGO stage, amount of residual disease, histology, performance status, and response at second look, while no influence was observed according to grade of tumor differentiation and age. Our results demonstrate the usefulness of doxorubicin in terms of surgical CR.
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Meister, Franziska Alexandra, Zoltan Czigany, Jan Bednarsch, Jörg Böcker, Iakovos Amygdalos, Daniel Antonio Morales Santana, Katharina Rietzler, et al. "Hypothermic Oxygenated Machine Perfusion of Extended Criteria Kidney Allografts from Brain Dead Donors: Protocol for a Prospective Pilot Study." JMIR Research Protocols 8, no. 10 (October 14, 2019): e14622. http://dx.doi.org/10.2196/14622.
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Background Kidney transplantation is the only curative treatment option for end-stage renal disease. The unavailability of adequate organs for transplantation has resulted in a substantial organ shortage. As such, kidney donor allografts that would have previously been deemed unsuitable for transplantation have become an essential organ pool of extended criteria donor allografts that are now routinely being transplanted on a global scale. However, these extended criteria donor allografts are associated with significant graft-related complications. As a result, hypothermic oxygenated machine perfusion (HOPE) has emerged as a powerful, novel technique in organ preservation, and it has recently been tested in preclinical trials in kidney transplantation. In addition, HOPE has already provided promising results in a few clinical series of liver transplantations where the liver was donated after cardiac death. Objective The present trial is an investigator-initiated prospective pilot study on the effects of HOPE on extended criteria donor allografts donated after brain death and used in kidney transplantation. Methods A total of 15 kidney allografts with defined inclusion/exclusion criteria will be submitted to two hours of HOPE via the renal artery before implantation, and are going to be compared to a case-matched group of 30 patients (1:2 matching) who had kidneys transplanted after conventional cold storage. Primary (posttransplant dialysis within 7 days) and secondary (postoperative complications, early graft function, duration of hospital and intensive care unit stay, and six-month graft survival) endpoints will be analyzed within a six-month follow-up period. The extent of ischemia-reperfusion injury will be assessed using kidney tissue, perfusate, and serum samples taken during the perioperative phase of kidney transplantation Results The results of this trial are expected in the first quarter of 2020 and will be presented at national and international scientific meetings and published in international peer-reviewed medical journals. The trial was funded in the third quarter of 2017 and patient enrollment is currently ongoing. Conclusions This prospective study is designed to explore the effects of HOPE on extended criteria donor kidney allografts donated after brain death. The present report represents the preresults phase. Trial Registration Clinicaltrials.gov NCT03378817; https://clinicaltrials.gov/ct2/show/NCT03378817
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Rousseau, P., F. Flamant, E. Quintana, P. A. Voute, and J. C. Gentet. "Primary chemotherapy in rhabdomyosarcomas and other malignant mesenchymal tumors of the orbit: results of the International Society of Pediatric Oncology MMT 84 Study." Journal of Clinical Oncology 12, no. 3 (March 1994): 516–21. http://dx.doi.org/10.1200/jco.1994.12.3.516.
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PURPOSE The MMT 84 multicentric prospective trial of the International Society of Pediatric Oncology (SIOP) was designed to (1) test the effectiveness of ifosfamide 3 g/m2 on days 1 and 2, vincristine 1.5 mg/m2 on days 1 and 14, and dactinomycin 0.9 mg/m2 on days 1 and 2 (IVA) repeated every 21 days; and (2) reduce late effects of treatment by reserving radiation therapy to the primary site for patients not achieving a complete response (CR) to primary chemotherapy. MATERIALS AND METHODS Between 1984 and 1989, the MMT 84 study registered 34 children with nonmetastatic rhabdomyosarcomas (RMSs) and other malignant mesenchymal tumors (MMTs) of the orbit in this trial. RESULTS The 4-year event-free survival rate is 62% +/- 9% (SD) and the 4-year survival rate 86% +/- 7% (SD). A total of 11 local recurrences occurred, 10 among 22 patients treated without initial radiation. Salvage of local failure was achieved in nine of 11 patients with the use of radiation and additional chemotherapy, but three later developed distant metastases and two have died. One isolated regional lymph node failure has occurred, while no patient relapsed with isolated distant metastases. Six of 12 patients who failed are alive with no evidence of disease from 16 to 50 months after relapse. The treatment was well tolerated in all patients, except for one with renal tubular acidosis and one who died of cardiotoxicity. Twelve patients remain in first remission without the use of radiation to the primary tumor from 27 to 84 months. CONCLUSION Despite a higher incidence of local recurrence when treated by primary chemotherapy, early survival rates were not compromised and a significant number of patients avoided the late effects of radiation. However, longer follow-up is required to assess the ultimate outcome of patients treated in this manner.
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Gnanenthiran, Sonali Rukshana, Claudio Borghi, Dylan Burger, Fadi Charchar, Neil R. Poulter, Markus P. Schlaich, Ulrike Muscha Steckelings, et al. "Prospective meta-analysis protocol on randomised trials of renin–angiotensin system inhibitors in patients with COVID-19: an initiative of the International Society of Hypertension." BMJ Open 11, no. 2 (February 2021): e043625. http://dx.doi.org/10.1136/bmjopen-2020-043625.
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IntroductionWhether ACE inhibitors (ACEi) or angiotensin II receptor blocker (ARB) therapy should be continued, initiated or ceased in patients with COVID-19 is uncertain. Given the widespread use of ACEi/ARBs worldwide, guidance on the use of these drugs is urgently needed. This prospective meta-analysis aims to pool data from randomised controlled trials (RCTs) to assess the safety and efficacy of ACEi/ARB therapy in adults infected with SARS-CoV-2.Methods and analysisRCTs will be eligible if they compare patients with COVID-19 randomised to ACEi/ARB continuation or commencement versuss no ACEi/ARB therapy; study duration ≥14 days; recruitment completed between March 2020 and May 2021. The primary outcome will be all-cause mortality at ≤30 days. Secondary outcomes will include mechanical ventilation, admission to intensive care or cardiovascular events at short-term follow-up (≤30 days) and all-cause mortality at longer-term follow-up (>1 month). Prespecified subgroup analyses will assess the effect of sex; age; comorbidities; smoking status; ethnicity; country of origin on all-cause mortality. A search of ClinicalTrials.gov has been performed, which will be followed by a formal search of trial registers, preprint servers, MEDLINE, EMBASE and Cochrane Central Register of Controlled Trials to identify RCTs that meet inclusion criteria. To date, a search of ClinicalTrials.gov identified 21 potentially eligible trials for this meta-analysis. We will request trial investigators/sponsors to contribute standardised grouped tabular outcome data.Ethics and disseminationEthics approval and informed consent will be the responsibility of the individual RCTs. Dissemination of results will occur by peer-reviewed publication. The results of our analysis can inform public health policy and clinical decision making regarding ACEi/ARB use in patients with COVID-19 on a global scale.
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Jayant, Kumar, Isabella Reccia, Francesco Virdis, and A. M. James Shapiro. "The Role of Normothermic Perfusion in Liver Transplantation (TRaNsIT Study): A Systematic Review of Preliminary Studies." HPB Surgery 2018 (May 17, 2018): 1–14. http://dx.doi.org/10.1155/2018/6360423.
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Introduction. The success of liver transplantation has been limited by the unavailability of suitable donor livers. The current organ preservation technique, i.e., static cold storage (SCS), is not suitable for marginal organs. Alternatively, normothermic machine perfusion (NMP) promises to recreate the physiological environment and hence holds promise for the better organ preservation. The objective of this systematic review is to provide an overview of the safety, benefits, and insight into the other potential useful parameters of NMP in the liver preservation. Material and Methods. We searched the current literature following registration in the International Prospective Register of Systematic Reviews (PROSPERO) with registration number CRD42018086034 for prospective trials comparing the role of NMP device to SCS in liver transplant by searching the PubMed, EMBASE, Cochrane, BIOSIS, Crossref, and Scopus databases and clinical trial registry. Results. The literature search identified five prospective clinical trials (four being early phase single institutional and single randomized multi-institutional) comparing 187 donor livers on NMP device to 273 donor livers on SCS. The primary outcome of interest was to assess the safety and graft survival at day 30 after transplant following NMP of the donor liver. Secondary outcomes included were early allograft dysfunction (EAD) in the first seven days; serum measures of liver functions as bilirubin, aspartate aminotransferase (AST), alanine amino transferase (ALT), alkaline phosphatase (ALP), and international normalized ratio (INR) on days 1–7; major complications as defined by a Clavien-Dindo score ≥ 3; and patient and graft survival and biliary complications at six months. The peaked median AST level between days 1 and 7 in the five trials was 417–1252 U/L (range 84–15009 U/L) while on NMP and 839–1474 U/L (range 153–8786 U/L) in SCS group. The median bilirubin level on day 7 ranged within 25–79 µmol/L (range 8–344 µmol/l) and 30–47.53 µmol/l (range 9–340 µmol/l) in NMP and SCS groups, respectively. A single case of PNF was reported in NMP group in the randomized trial while none of the other preliminary studies reported any in either group. There was intertrial variability in EAD which ranged within 15–56% in NMP group while being within 23–37% in SCS group. Biliary complications observed in NMP group ranged from 0 to 20%. Single device malfunction was reported in randomized controlled trial leading to renouncement of transplant while none of the other trials reported any machine failure, although two user related device errors inadvertent were reported. Conclusion. This review outlines that NMP not only demonstrated safety and efficacy but also provided the favourable environment of organ preservation, repair, and viability assessment to donor liver prior to the transplantation with low rate of posttransplantation complication as PNF, EAD, and biliary complication; however further studies are needed to broaden our horizon.
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Loehrer, P. J., L. H. Einhorn, P. J. Elson, E. D. Crawford, P. Kuebler, I. Tannock, D. Raghavan, R. Stuart-Harris, M. F. Sarosdy, and B. A. Lowe. "A randomized comparison of cisplatin alone or in combination with methotrexate, vinblastine, and doxorubicin in patients with metastatic urothelial carcinoma: a cooperative group study." Journal of Clinical Oncology 10, no. 7 (July 1992): 1066–73. http://dx.doi.org/10.1200/jco.1992.10.7.1066.
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PURPOSE A prospective randomized trial was performed to determine if the addition of methotrexate, vinblastine, and doxorubicin to cisplatin (M-VAC) imparted a response rate or a survival advantage over single-agent cisplatin in patients with advanced urothelial carcinoma. PATIENTS AND METHODS From October 1984 through May 1989, 269 patients with advanced urothelial carcinoma were entered onto this international intergroup trial and randomized to receive intravenous (IV) cisplatin (70 mg/m2) alone or with methotrexate (30 mg/m2 on days 1, 15, 22), vinblastine (3 mg/m2 on days 2, 15, 22) plus doxorubicin (30 mg/m2 on day 2). Cycles were repeated every 28 days until tumor progression or a maximum of six cycles. There were 246 fully assessable patients of whom 126 were randomized to cisplatin alone and 120 were randomized to the M-VAC regimen. RESULTS As expected, the M-VAC regimen was associated with a greater toxicity, especially leukopenia, mucositis, granulocytopenic fever, and drug-related mortality. Response rates were superior for the M-VAC regimen compared with single-agent cisplatin (39% v 12%; P less than .0001). Similarly, the progression-free survival (10.0 v 4.3 months) and overall survival (12.5 v 8.2 months) were significantly greater for the combined therapy arm. CONCLUSION Although a more toxic regimen, we found M-VAC to be superior to single-agent cisplatin with respect to response rate, duration of remission, and overall survival in patients with advanced urothelial carcinoma.
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Arthur, Adam S., Andy Molyneux, Alexander L. Coon, Isil Saatci, Istvan Szikora, Feyyaz Baltacioglu, Ali Sultan, et al. "The safety and effectiveness of the Woven EndoBridge (WEB) system for the treatment of wide-necked bifurcation aneurysms: final 12-month results of the pivotal WEB Intrasaccular Therapy (WEB-IT) Study." Journal of NeuroInterventional Surgery 11, no. 9 (April 16, 2019): 924–30. http://dx.doi.org/10.1136/neurintsurg-2019-014815.
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IntroductionThe Woven EndoBridge Intrasaccular Therapy (WEB-IT) Study is a pivotal, prospective, single-arm, investigational device exemption study designed to evaluate the safety and effectiveness of the WEB device for the treatment of wide-neck bifurcation aneurysms.MethodsOne-hundred and fifty patients with wide-neck bifurcation aneurysms were enrolled at 21 US and six international centers. Angiograms from the index procedure, and 6-month and 1-year follow-up visits were all reviewed by a core laboratory. All adverse events were reviewed and adjudicated by a clinical events adjudicator. A data monitoring committee provided oversight during the trial to ensure subject safety.ResultsOne-hundred and forty-eight patients received the WEB implant. One (0.7%) primary safety event occurred during the study—a delayed ipsilateral parenchymal hemorrhage—on postoperative day 22. No primary safety events occurred after 30 days through 1 year. At the 12-month angiographic follow-up, 77/143 patients (53.8%) had complete aneurysm occlusion. Adequate occlusion was achieved in 121/143 (84.6%) subjects.ConclusionsThe prespecified safety and effectiveness endpoints for the aneurysms studied in the WEB-IT trial were met. The results of this trial suggest that the WEB device provides an option for patients with wide-neck bifurcation aneurysms that is as effective as currently available therapies and markedly safer.Trial registration numberNCT02191618
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Vitolo, Umberto, Annalisa Chiappella, Andrés J. M. Ferreri, Maurizio Martelli, Ileana Baldi, Monica Balzarotti, Chiara Bottelli, et al. "First-Line Treatment for Primary Testicular Diffuse Large B-Cell Lymphoma With Rituximab-CHOP, CNS Prophylaxis, and Contralateral Testis Irradiation: Final Results of an International Phase II Trial." Journal of Clinical Oncology 29, no. 20 (July 10, 2011): 2766–72. http://dx.doi.org/10.1200/jco.2010.31.4187.
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Purpose Primary testicular lymphoma (PTL) has poor prognosis with failures in contralateral testis, CNS, and extranodal sites. To prevent these events, we designed an international phase II trial (International Extranodal Lymphoma Study Group 10 [IELSG-10]) that addressed feasibility and activity of conventional chemoimmunotherapy associated with CNS prophylaxis and contralateral testis irradiation. The trial was conducted by the IELSG and the Italian Lymphoma Foundation. Patients and Methods Fifty-three patients (age 22 to 79 years) with untreated stage I or II PTL were treated with six to eight courses of rituximab added to cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) every 21 days (R-CHOP21); four doses of intrathecal methotrexate (IT-MTX) and radiotherapy (RT) to the contralateral testis (30 Gy) for all patients and to regional lymph nodes (30 to 36 Gy) for stage II disease. Results All patients received R-CHOP21, 50 received CNS prophylaxis, and 47 received testicular RT. With a median follow-up of 65 months, 5-year progression-free survival and overall survival rates were 74% (95% CI, 59% to 84%) and 85% (95% CI, 71% to 92%), respectively. Ten patients relapsed or progressed: two in lymph nodes, five in extranodal organs, and three in the CNS. The 5-year cumulative incidence of CNS relapse was 6% (95% CI, 0% to 12%). No contralateral testis relapses occurred. Ten patients died: lymphoma (n = 6), secondary leukemia (n = 2), heart failure (n = 1), and gastric cancer (n = 1). Grade 3 to 4 toxicities were neutropenia, 28%; infections, 4%; and neurologic, 13%. No deaths occurred as a result of toxicity. Conclusion This international prospective trial shows that combined treatment with R-CHOP21, IT-MTX, and testicular RT was associated with a good outcome in patients with PTL. RT avoided contralateral testis relapses, but CNS prophylaxis deserves further investigation.
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de Havenon, Adam, Greg Stoddard, Monica Saini, Ka-Ho Wong, David Tirschwell, and Phillip Bath. "Increased blood pressure variability after acute ischemic stroke increases the risk of death: A secondary analysis of the Virtual International Stroke Trial Archive." JRSM Cardiovascular Disease 8 (January 2019): 204800401985649. http://dx.doi.org/10.1177/2048004019856496.
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Background Despite promising epidemiological data, it remains unclear if increased blood pressure variability is associated with death after acute ischemic stroke. Our objective was to examine this association in a large cohort of acute ischemic stroke patients. Methods We conducted a retrospective analysis of anonymized, pooled, participant data from the Virtual International Stroke Trial Archive. We included patients with a 90-day modified Rankin Scale and blood pressure readings in the 24 h after study enrollment. The exposure was blood pressure variability during the day after study enrollment, calculated for the systolic and diastolic blood pressure using six statistical methodologies. The primary outcome was death within 90 days of stroke onset. Results Our cohort comprised 1891 patients of whom 277 (14.7%) died within 90 days. All indices of blood pressure variability were higher in patients who died, but the difference was more pronounced for systolic than diastolic blood pressure variability (systolic standard deviation for alive versus dead patients = 13.4 versus 15.9 mmHg, p < 0.001). Similar results were found in logistic regression models fit to the outcome of death, but only systolic blood pressure variability remained significant in adjusted models (Odds Ratio for death when comparing highest to lowest tercile of systolic blood pressure variability = 1.41–1.89, p < 0.03 for all). Conclusions and relevance: These results reinforce prior studies that found increased blood pressure variability is associated with worse neurologic outcome after stroke. These data should help guide research on blood pressure variability after stroke and advocate for the inclusion of death as a clinical outcome in future studies that therapeutically reduce blood pressure variability.
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Cappellini, Maria Domenica, and Ali T. Taher. "The use of luspatercept for thalassemia in adults." Blood Advances 5, no. 1 (January 12, 2021): 326–33. http://dx.doi.org/10.1182/bloodadvances.2020002725.
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AbstractLuspatercept is an activin receptor ligand trap that has been shown to enhance late-stage erythropoiesis in animal models of β-thalassemia. A multicenter, international, phase 2 dose-finding study was initiated in adult patients with β-thalassemia, either non–transfusion-dependent thalassemia (NTDT) or transfusion-dependent thalassemia (TDT). Positive results of the phase 2 study paved the way to a randomized phase 3 clinical trial (BELIEVE) to assess the efficacy and safety of luspatercept. The BELIEVE trial is a randomized, double-blind, placebo-controlled phase 3 trial. Three hundred thirty-six patients aged ≥18 years with TDT (regularly transfused, 6-20 red blood cell units within 24 weeks before randomization) were included in the trial. Patients received luspatercept or placebo subcutaneously every 21 days for ≥48 weeks and best supportive care. Forty-eight of 224 patients (21.4%) in the luspatercept group achieved the primary end points (≥33% reduction in transfusion burden) compared with those in the placebo group (4.5%; P < .001). Moreover, more patients had a ≥33% reduction in transfusion burden during any rolling 12-week interval (70.5% vs 29.5%) or any 24-week interval (41.1% vs 2.7%) with luspatercept than with the placebo. Transfusion independence was achieved by 11% of patients in the luspatercept group. Transient adverse events were more frequent with luspatercept than with placebo, but were manageable. Luspatercept was approved by the US Food and Drug Administration in 2019 and by the European Medicines Agency in 2020. The luspatercept trial is registered on www.clinicaltrials.gov at #NCT01749540 and the BELIEVE trial at #NCT02604433.
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Badgwell, Brian D., Naruhiko Ikoma, Mariela A. Blum Murphy, Xuemei Wang, Jeannelyn Estrella, Sinchita Roy-Chowdhuri, Prajnan Das, Bruce D. Minsky, Paul F. Mansfield, and Jaffer A. Ajani. "A phase II trial of cytoreduction, gastrectomy, and hyperthermic intraperitoneal perfusion with chemotherapy for patients with gastric cancer and stage IV peritoneal disease." Journal of Clinical Oncology 38, no. 4_suppl (February 1, 2020): 361. http://dx.doi.org/10.1200/jco.2020.38.4_suppl.361.
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361 Background: Current national guidelines do not include hyperthermic intraperitoneal chemoperfusion (HIPEC) as treatment for gastric cancer, and there are no completed clinical trials of cytoreduction, gastrectomy, and HIPEC from the U.S. However, recent international studies report long-term survival rates of approximately 20% with cytoreduction/gastrectomy/HIPEC. Methods: Patients with gastric adenocarcinoma and positive peritoneal cytology or carcinomatosis who had completed systemic chemotherapy and laparoscopic HIPEC underwent cytoreduction, gastrectomy, and HIPEC with 30 mg mitomycin C and 200 mg cisplatin. The primary end point was overall survival (OS), with secondary end points of safety and postoperative complications. Results: We enrolled 20 patients from 9/2016 to 3/2019, with a median age of 58 years (range, 20-75 years). Six patients had positive cytology only at diagnosis of stage IV disease, whereas 14 had carcinomatosis. All patients were treated with systemic chemotherapy with a median of 8 cycles (range, 5-11 cycles) and at least one laparoscopic HIPEC. The median peritoneal carcinomatosis index at cytoreduction/gastrectomy/HIPEC was 2 (range, 0-13). After surgery, the 90-day morbidity and mortality rates were 70% and 0%, respectively. Median length of hospital stay was 13 days (range, 7-23 days). Median follow-up was 1.8 years. Median OS from the date of diagnosis of metastatic disease was 2.1 years. Median OS from the date of cytoreduction, gastrectomy, and HIPEC was 1.4 years. One, 2, and 3-year OS rates from the diagnosis of metastatic disease are 90%, 54%, and 29%. Conclusions: Survival rates for patients with gastric adenocarcinoma and peritoneal disease treated with cytoreduction, gastrectomy, and HIPEC are encouraging; our early results are similar to those of recent prospective registry studies. Cooperative group trials should be supported and will be required to confirm survival and safety outcomes. Clinical trial information: NCT02891447.
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Dirksen, Uta, Andreas Ranft, Daniel Baumhoer, Henk van den Berg, Bénédicte Brichard, Hans-Theodor Eich, Hans Gelderblom, et al. "Association of treatment delays with an unfavorable outcome in patients with localized Ewing sarcoma: A retrospective analysis of data from the GPOH Euro-E.W.I.N.G.99 trial." Journal of Clinical Oncology 39, no. 15_suppl (May 20, 2021): 11502. http://dx.doi.org/10.1200/jco.2021.39.15_suppl.11502.
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11502 Background: Outcome in EwS has improved by the implementation of dose or time intense systemic treatment. Aim of the study was evaluate whether treatment delays have impact on outcome of patients with localized Ewing sarcoma (EWS). Methods: Data from 692 patients with a tumor of the extremities, the pelvis, the chest wall and the trunk registered in the international database of the German Society for Pediatric Oncology and Hematology (GPOH) and treated in the Euro-E.W.I.N.G. 99 trial (NCT00020566) were analyzed. All patients underwent surgical treatment after induction chemotherapy. The optimal interval cut-off values for survival analyses were calculated with receiver operating characteristics curves. Hazard ratios (HR) were estimated with respective 95% confidence intervals (CI) in multivariate Cox regression models. Results: As per protocol, patients were to receive six cycles of VIDE induction chemotherapy in 21-day intervals. The duration between induction cycles as per protocol was fulfilled in only 5% of patients. In 72% of patients, the average interval duration between induction chemotherapy cycles was 25 days. Median interval between day 1 of the first induction chemotherapy cycle and definitive tumor surgery was 141 (IQR, 133 – 153) days in patients receiving six VIDE cycles prior to surgery. The optimal cut-off value for survival analyses in these patients amounted to 150 days. Patients with a duration of induction chemotherapy > 150 days were at higher risk to develop an event (HR, 1.546; 95% CI, 1.103 – 2.166) and had a higher risk of death (HR, 1.574; 95% CI, 1.095 – 2.262), compared to patients with a duration of induction chemotherapy < 150 days. Patients with delays during the induction chemotherapy also experienced a significant delay between VIDE 6 and surgery (36 vs. 27 days, p < 0.001) and were treated significantly more often at smaller low-volume centers (63% vs. 48%, p = 0.005). Patients with a prolonged interval > 21 days between surgery and day one of postoperative chemotherapy were at a higher risk to develop an event (HR, 1.406; 95% CI, 1.011 – 1.955), and also had a significantly higher rate of postoperative complications (26% vs. 11%, p < 0.001), compared to patients with a shorter interval. Conclusions: Delays between induction chemotherapy and surgery and between surgery and consolidation chemotherapy are independently associated with a poor outcome in patients with localized EWS. Our results also underscore the need to treat EWS patients in larger and experienced sarcoma centers. The implementation of new and standardized methods in the operative strategy and optimized supportive care during systemic therapy are required to reduce perioperative morbidity and treatment delays.
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Wils, J. A., J. M. Bliss, M. Marty, G. Coombes, C. Fontaine, F. Morvan, T. Olmos, et al. "Epirubicin Plus Tamoxifen Versus Tamoxifen Alone in Node-Positive Postmenopausal Patients With Breast Cancer: A Randomized Trial of the International Collaborative Cancer Group." Journal of Clinical Oncology 17, no. 7 (July 1999): 1988. http://dx.doi.org/10.1200/jco.1999.17.7.1988.
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PURPOSE: To assess whether the addition of epirubicin (EPI) therapy to prolonged treatment with tamoxifen (TAM) improves relapse-free and overall survival in postmenopausal women with node-positive primary breast cancer. PATIENTS AND METHODS: Six hundred four patients entered onto a randomized clinical trial were allocated to receive TAM 20 mg/d for 4 years or TAM 20 mg/d for 4 years plus EPI 50 mg/m2 intravenously on days 1 and 8 every 4 weeks for six cycles. Analysis was performed according to allocated treatment, with all randomized patients included (intention to treat), irrespective of eligibility status. RESULTS: After a median follow-up period of 5.7 years, an improvement in relapse-free survival (RFS) was observed for the TAM and EPI–treated patients, compared with those who received TAM alone. The unadjusted hazard ratio was 0.72 (95% confidence interval, 0.54 to 0.96), with a corresponding reduction in the odds of recurrence of 27.9% (SD, 12.3), which was statistically significant (P = .023). Adjustment for prognostic and/or predictive factors did not materially affect the hazard ratio. No difference was observed in terms of overall survival (reduction in odds of death, 11.9% [SD, 16.3]; P = .46). Combined chemohormonal treatment was associated with a higher incidence of acute side effects but without a clear increase in long-term cardiotoxicity. Twelve nonbreast second malignancies, including five hematologic malignancies (two of which were cases of acute myelogenous leukemia), were observed. CONCLUSION: The data show that combined chemohormonal treatment reduces the risk of relapse in postmenopausal patients with node-positive breast cancer. No evidence was found, however, for an improvement in overall survival. The size of benefit observed for both outcomes was consistent with that reported in the Early Breast Cancer Trialists' Collaborative Group overview. The trial presented here, however, provides the first report of an improvement in RFS associated with the provision of a single cytotoxic drug in addition to prolonged TAM.
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Zinzani, Pier Luigi, Massimo Magagnoli, Luciano Moretti, Amalia De Renzo, Raffaele Battista, Alfonso Zaccaria, Luciano Guardigni, et al. "Randomized Trial of Fludarabine Versus Fludarabine and Idarubicin as Frontline Treatment in Patients With Indolent or Mantle-Cell Lymphoma." Journal of Clinical Oncology 18, no. 4 (February 14, 2000): 773. http://dx.doi.org/10.1200/jco.2000.18.4.773.
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PURPOSE: A first comparative trial of fludarabine (FLU) alone versus FLU plus idarubicin (FLU-ID) for indolent or mantle-cell lymphomas. PATIENTS AND METHODS: From September 1995 to July 1998, 199 patients aged 25 to 65 years (median, 54 years) with newly diagnosed stages II to IV indolent or mantle-cell lymphomas (standard risk according to the International Prognostic Index) were enrolled onto a multicenter, 1:1 randomized study. Of the 199 patients who were able to be assessed, 101 were assigned to the FLU group (six monthly cycles of FLU 25 mg/m2/d on days 1 through 5) and 98 to the FLU-ID group (six monthly cycles of FLU 25 mg/m2/d on days 1 through 3 and idarubicin 12 mg/m2 on day 1). RESULTS: In the FLU group, complete response (CR) and partial response rates were 47% and 37%, respectively, whereas in the FLU-ID group, they were 39% and 42%, respectively. In-depth analysis of the CR rate with respect to histologic type showed that FLU seemed to be superior to FLU-ID in treating follicular lymphomas (60% v 40%, respectively), whereas FLU-ID seemed to be more effective than FLU in treating nonfollicular lymphomas (small lymphocytic, 43% v 29%, respectively; immunocytoma, 38% v 23%, respectively; P = not significant), excluding the mantle-cell subset (in which there was no difference between the two groups). No striking differences were observed between the two protocols in terms of overall response or toxicity, which was generally mild. However, with a median follow-up of 19 months, only 29 patients (62%) who received FLU alone have maintained their initial CR, compared with 32 (84%) of those who received FLU-ID therapy (P = .021). CONCLUSION: Although the FLU-ID regimen may not significantly improve the induction of CR in most indolent-lymphoma patients, our preliminary data do suggest that, with respect to FLU alone, it may be capable of conferring a longer-lasting CR and that it might be superior in terms of CR rate in small lymphocytic and immunocytoma subtypes.
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González-Barca, Eva, Miguel A. Canales, Antonio Salar, Secundino Ferrer, Eva Domingo-Domenech, María-Jesús Vidal, Carlos Grande, et al. "Long-Term Follow-Up of a Phase II Trial of Six Cycles of Dose-Dense R-CHOP-14 for First-Line Treatment of Diffuse Large B-Cell Lymphoma in Young and Elderly Patients." Acta Haematologica 136, no. 2 (2016): 76–84. http://dx.doi.org/10.1159/000444625.
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Background/Aims: Rituximab-cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) every 14 days seems to achieve better outcomes than R-CHOP every 21 days in diffuse large B-cell lymphoma (DLBCL) patients. Currently, the standard regimen is R-CHOP every 21 days. Methods: This is a phase II clinical trial of treatment with 6 cycles of R-CHOP-14 with pegfilgrastim support in 2 populations of previously untreated DLBCL patients aged ≥65 years (n = 73) or <65 years (n = 51) with low-risk International Prognostic Index scores (0-2). Results: With a median follow-up of 63.7 months, the 5-year event-free survival rate was 53.8% in patients aged ≥65 years and 71.0% in patients aged <65 years. The 5-year overall survival rate was 71.4 and 89.8%, respectively. The complete remission rate was 69.9% for older and 80.4% for younger patients. The median relative dose intensity of cytotoxic drugs was 143.2% in the elderly and 149.1% in the young patients. Febrile neutropenia was the most common grade 3-4 adverse event, being higher in elderly patients (21.3 vs. 9.3%). Eight deaths (7 in elderly patients) were considered treatment related. Conclusion: In conclusion, the R-CHOP-14 regimen is feasible and very active, though it is more toxic in elderly patients mainly due to an increased incidence of infections. New strategies, such as new monoclonal antibodies or new targeted therapies, are needed to improve the outcomes of DLBCL patients.
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Onyamboko, M. A., C. I. Fanello, K. Wongsaen, J. Tarning, P. Y. Cheah, K. A. Tshefu, A. M. Dondorp, F. Nosten, N. J. White, and N. P. J. Day. "Randomized Comparison of the Efficacies and Tolerabilities of Three Artemisinin-Based Combination Treatments for Children with Acute Plasmodium falciparum Malaria in the Democratic Republic of the Congo." Antimicrobial Agents and Chemotherapy 58, no. 9 (July 7, 2014): 5528–36. http://dx.doi.org/10.1128/aac.02682-14.
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ABSTRACTAn open-label, randomized controlled trial was carried out in 2011–2012 in the Democratic Republic of the Congo to test the efficacy, safety, and tolerability of the artemisinin-based combination treatments dihydroartemisinin-piperaquine, amodiaquine-artesunate, and artemether-lumefantrine. Six hundred eighty-four children aged 3 to 59 months with uncomplicatedPlasmodium falciparummalaria were randomly allocated to each study arm. Children were hospitalized for 3 days, given supervised treatment, and followed up weekly for 42 days. All regimens were well tolerated and rapidly effective. The median parasitemia clearance half-life was 2.2 h, and half-lives were similar between arms (P= 0.19). The PCR-uncorrected cure rates by day 42 were 73.0% for amodiaquine-artesunate, 70.2% for artemether-lumefantrine, and 86.3% for dihydroartemisinin-piperaquine (P= 0.001). Early treatment failure occurred in three patients (0.5%), one in each arm. The PCR-corrected cure rates were 93.4% for amodiaquine-artesunate, 92.7% for artemether-lumefantrine, and 94.3% for dihydroartemisinin-piperaquine (P= 0.78). The last provided a longer posttreatment prophylactic effect than did the other two treatments. The day 7 plasma concentration of piperaquine was below 30 ng/ml in 47% of the children treated with dihydroartemisinin-piperaquine, and the day 7 lumefantrine concentration was below 280 ng/ml in 37.0% of children who received artemether-lumefantrine. Thus, although cure rates were all satisfactory, they could be improved by increasing the dose. (This study has been registered with the International Standard Randomized Controlled Trial Number Register [www.isrctn.org] under registration no. ISRCTN20984426.)
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Souto, Joan C., Artur Oliver, Isabel Montserrat, José Mateo, Anna Sureda, and Jordi Fontcuberta. "Lack of Effect of Influenza Vaccine on Anticoagulation by Acenocoumarol." Annals of Pharmacotherapy 27, no. 3 (March 1993): 365–68. http://dx.doi.org/10.1177/106002809302700322.
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OBJECTIVE: To analyze the effects of influenza vaccine on patients receiving chronic anticoagulant therapy with acenocoumarol. DESIGN: A prospective trial. SETTING: Hospital de la Santa Creu i Sant Pau, Barcelona. PATIENTS: Forty-three patients who received acenocoumarol, had stable levels of International Normalized Ratio (INR), and did not need dosage modification for four months before entering the study. INTERVENTION: A study of anticoagulation levels measured by INR at 7, 15, and 30 days from administration of the trivalent vaccine from the 91–92 campaign was conducted. MAIN OUTCOME MEASURES: Comparison was made between basal values (day 0) and anticoagulation levels at 7, 15, and 30 days from vaccine administration by means of a repeated-measures ANOVA. RESULTS: Nine patients (21 percent) had INR levels out of the therapeutic range during the study period. INR increased in three of these patients and decreased in six. There were no significant intraindividual changes in INR values during the time period analyzed (p=0.125). No hemorrhagic or thrombotic manifestations occurred and no significant changes in renal or hepatic biochemistry were observed. CONCLUSIONS: Influenza vaccine does not modify acenocoumarol activity in patients receiving long-term anticoagulant therapy.
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Howard, Virginia J., Ale Algra, George Howard, Leo H. Bonati, Gert J. de Borst, Richard Bulbulia, David Calvet, et al. "Absence of Consistent Sex Differences in Outcomes From Symptomatic Carotid Endarterectomy and Stenting Randomized Trials." Stroke 52, no. 2 (February 2021): 416–23. http://dx.doi.org/10.1161/strokeaha.120.030184.
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Background and Purpose: CREST (Carotid Revascularization Endarterectomy Versus Stenting Trial) reported a higher periprocedural risk for any stroke, death, or myocardial infarction for women randomized to carotid artery stenting (CAS) compared with women randomized to carotid endarterectomy (CEA). No difference in risk by treatment was detected for women relative to men in the 4-year primary outcome. We aimed to conduct a pooled analysis among symptomatic patients in large randomized trials to provide more precise estimates of sex differences in the CAS-to-CEA risk for any stroke or death during the 120-day periprocedural period and ipsilateral stroke thereafter. Methods: Data from the Carotid Stenosis Trialists’ Collaboration included outcomes from symptomatic patients in EVA-3S (Endarterectomy Versus Angioplasty in Patients With Symptomatic Severe Carotid Stenosis), SPACE (Stent-Protected Angioplasty Versus Carotid Endarterectomy in Symptomatic Patients), ICSS (International Carotid Stenting Study), and CREST. The primary outcome was any stroke or death within 120 days after randomization and ipsilateral stroke thereafter. Event rates and relative risks were estimated using Poisson regression; effect modification by sex was assessed with a sex-by-treatment-by-trial interaction term, with significant interaction defined a priori as P ≤0.10. Results: Over a median 2.7 years of follow-up, 433 outcomes occurred in 3317 men and 1437 women. The CAS-to-CEA relative risk of the primary outcome was significantly lower for women compared with men in 1 trial, nominally lower in another, and nominally higher in the other two. The sex-by-treatment-by-trial interaction term was significant ( P =0.065), indicating heterogeneity among trials. Contributors to this heterogeneity are primarily differences in periprocedural period. When the trials are nevertheless pooled, there were no significant sex differences in risk in any follow-up period. Conclusions: There were significant differences between trials in the magnitude of sex differences in treatment effect (CAS-to-CEA relative risk), indicating pooling data from these trials to estimate sex differences might not be valid. Whether sex is acting as an effect modifier of the CAS-to-CEA treatment effect in symptomatic patients remains uncertain. Registration: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT00190398 (EVA-3S) and NCT00004732 (CREST). URL: https://www.isrctn.com ; Unique identifier: ISRCTN57874028 (SPACE) and ISRCTN25337470 (ICSS).
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Rudberg, Ann-Sofie, Eivind Berge, Anders Gustavsson, Per Näsman, and Erik Lundström. "Long-term health-related quality of life, survival and costs by different levels of functional outcome six months after stroke." European Stroke Journal 3, no. 2 (January 9, 2018): 157–64. http://dx.doi.org/10.1177/2396987317753444.
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Introduction Information about the impact of functional outcome after stroke is currently missing on health-related quality of life, survival and costs. This information would be valuable for health economic evaluations and for allocation of resources in stroke health care. Patients and methods Data on 297 Swedish patients included in the Third International Stroke Trial were analysed including functional outcome at six months (measured by Oxford Handicap Scale), health-related quality of life up to 18 months (EQ-5D-3L) and survival up to 36 months. We used record linkage to collect data on costs up to 36 months, using national patient registers. Results Patients with a better functional outcome level at six months had a significantly better health-related quality of life at 18 months ( p < 0.05), better long-term survival ( p < 0.05) and lower costs ( p < 0.001), for all time points up to 36 months. The difference in costs was mainly due to differences in days spent in hospital ( p < 0.005). Discussion This study showed an association between functional outcome at six months and health-related quality of life up to 18 months, and costs up to 36 months. Conclusion Functional outcome six months after stroke is an important determinant of health-related quality of life, survival and costs over 36 months. Effective interventions aimed at reducing short-term disability levels are therefore also expected to reduce the overall burden of stroke.
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Yadav, Ramakant, and S. K. Shukla. "Propranolol versus topiramate in prophylaxis of migraines among children and adolescents: a randomized, double-blind clinical trial." International Journal of Research in Medical Sciences 5, no. 10 (September 28, 2017): 4307. http://dx.doi.org/10.18203/2320-6012.ijrms20174480.
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Background: Migraine is a common health problem in children and adolescents. This study compares the efficacy and safety of propranolol and topiramate in preventing migraine among children and adolescents.Methods: Seventy-six patients (10-18 years of age) with migraine without auras defined by the 2004 International Headache society criteria were included in a prospective double blind clinical trial were allocated to receive propranolol (0.5-2mg/kg per day) or topiramate (1-2mg/kg per day). The primary outcome measure was reduction in 50 % or more headache days in comparison to baseline headache frequency per month. Secondary outcome measures were headache related disability, migraine intensity and duration. Efficacy measures were recorded at the baseline and at 12 weeks of prophylactic treatment.Results: In this study total of 76 patients with mean age of 12.43 years were evaluated, 40 in the propranolol group and 36 in the topiramate group. At the 12-week, the percentage of patients who had a relative reduction of 50% or more in the number of headache days were 67.5% patients in the propranolol group and 75.0% patients in the topiramate group. The monthly migraine frequency, headache related disability, intensity and duration were significantly decreased in both the propranolol and topiramate groups when compared to the baseline. No significant difference was observed between these two groups in term of reduction of frequency, headache related disability, severity and duration of attack. Fatigue, hypotension and exercise induced asthma were main side effects in propranolol group and weight loss, fatigue and loss of appetite, paresthesias in topiramate group.Conclusions: Propranolol and topiramate were found effective and safe for the prevention of paediatric migraines.
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Leonard, John P., Sin-Ho Jung, Jeffrey Johnson, Brandelyn N. Pitcher, Nancy L. Bartlett, Kristie A. Blum, Myron Czuczman, Jeffrey K. Giguere, and Bruce D. Cheson. "Randomized Trial of Lenalidomide Alone Versus Lenalidomide Plus Rituximab in Patients With Recurrent Follicular Lymphoma: CALGB 50401 (Alliance)." Journal of Clinical Oncology 33, no. 31 (November 1, 2015): 3635–40. http://dx.doi.org/10.1200/jco.2014.59.9258.
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Purpose Lenalidomide and rituximab (LR) are active agents in follicular lymphoma (FL). Combination regimens have not been previously assessed in randomized studies. Patients and Methods The Cancer and Leukemia Group B (Alliance) 50401 trial is a randomized phase II trial studying rituximab (375 mg/m2 weekly for 4 weeks), lenalidomide (15 mg per day on days 1 to 21, followed by 7 days of rest, in cycle 1 and then 20 mg per day on days 1 to 21, followed by 7 days of rest, in cycles 2 to 12), or LR. The rituximab-alone arm was discontinued as a result of poor accrual. Eligibility included recurrent FL and prior rituximab with time to progression of ≥ 6 months from last dose. Aspirin or heparin was recommended for patients at high thrombosis risk. Results Ninety-one patients (lenalidomide, n = 45; LR, n = 46) received treatment; median age was 63 years (range, 34 to 89 years), and 58% were intermediate or high risk according to the Follicular Lymphoma International Prognostic Index. In the lenalidomide and LR arms, grade 3 to 4 adverse events occurred in 58% and 53% of patients, with 9% and 11% of patients experiencing grade 4 toxicity, respectively; grade 3 to 4 adverse events included neutropenia (16% v 20%, respectively), fatigue (9% v 13%, respectively), and thrombosis (16% [n = 7] v 4% [n = 2], respectively; P = .157). Thirty-six percent of lenalidomide patients and 63% of LR patients completed 12 cycles. Lenalidomide alone was associated with more treatment failures, with 22% of patients discontinuing treatment as a result of adverse events. Dose-intensity exceeded 80% in both arms. Overall response rate was 53% (20% complete response) and 76% (39% complete response) for lenalidomide alone and LR, respectively (P = .029). At the median follow-up of 2.5 years, median time to progression was 1.1 year for lenalidomide alone and 2 years for LR (P = .0023). Conclusion LR is more active than lenalidomide alone in recurrent FL with similar toxicity, warranting further study in B-cell non-Hodgkin lymphoma as a platform for addition of novel agents.
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Dummer, Reinhard, Pietro Quaglino, Jürgen C. Becker, Baktiar Hasan, Matthias Karrasch, Sean Whittaker, Stephen Morris, et al. "Prospective International Multicenter Phase II Trial of Intravenous Pegylated Liposomal Doxorubicin Monochemotherapy in Patients With Stage IIB, IVA, or IVB Advanced Mycosis Fungoides: Final Results From EORTC 21012." Journal of Clinical Oncology 30, no. 33 (November 20, 2012): 4091–97. http://dx.doi.org/10.1200/jco.2011.39.8065.
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PurposeMycosis fungoides (MF) is the most common primary cutaneous T-cell lymphoma. There is a need for multicenter trials involving defined patient populations using rigorous assessment criteria. We have investigated pegylated liposomal doxorubicin (PLD) in a clearly defined patient population with advanced MF.Patients and MethodsEligible patients had stage IIB, IVA, or IVB MF, refractory or recurrent after at least two previous systemic therapies. Patients were registered to receive a maximum of six cycles of PLD 20 mg/m2on days 1 and 15, every 28 days (one cycle). The primary end point was response rate (RR).ResultsNine centers recruited 49 eligible patients. The median number of chemotherapy cycles received was five. There were no grade 3 to 4 hematologic toxicities. Grade 3 or 4 nonhematologic/nonbiochemical toxicities included cardiac symptom (2%), allergy/hypersensitivity (2%), constitutional symptom (4%), hand and foot reaction (2%), other dermatologic toxicity (6%), other GI toxicity (4%), infection (4%), pulmonary embolism (2%), and cardiac ischemia (2%). Of 49 patients, 20 (40.8%) were responders (complete clinical response [CCR] or partial response [PR] as overall response): three (6.1%) experienced CCRs, and 17 (34.7%) experienced PRs. A 50% or greater reduction of cutaneous manifestations was observed in 26 (60.5%) of 43 assessable patients. Two early deaths were reported, resulting from related cardiovascular toxicity and disease progression. The lower limit of the one-sided 90% CI for RR was 31.2%. Median time to progression and median duration of response were 7.4 and 6 months, respectively.ConclusionPLD has an acceptable safety profile in patients with advanced MF. The efficacy of PLD seems promising.
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Rossi, J. F., A. Van Hoof, K. De Boeck, S. A. Johnson, D. Bron, C. Foussard, T. A. Lister, et al. "Efficacy and Safety of Oral Fludarabine Phosphate in Previously Untreated Patients With Chronic Lymphocytic Leukemia." Journal of Clinical Oncology 22, no. 7 (April 1, 2004): 1260–67. http://dx.doi.org/10.1200/jco.2004.05.012.
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Purpose A prospective, multicenter, open-label, phase II clinical trial to assess oral fludarabine phosphate treatment in terms of safety, efficacy, and quality of life. Reference to a historical group of patients treated with the intravenous (IV) formulation allowed the two formulations to be compared. Patients and Methods Patients with previously untreated B-cell chronic lymphocytic leukemia received 10-mg tablets of fludarabine phosphate to a dose of 40 mg/m2/d for 5 days, repeated every 4 weeks, for a total of six to eight cycles. Efficacy was assessed using International Workshop on Chronic Lymphocytic Leukemia and National Cancer Institute criteria for response. Safety monitoring included WHO toxicity grading for adverse events. Quality of life was also assessed. Results Eighty-one patients received treatment. According to International Workshop on Chronic Lymphocytic Leukemia criteria, the overall response rate was 71.6% (complete remission, 37.0%; partial remission, 34.6%). The response rate using National Cancer Institute criteria was 80.2% (complete remission, 12.3%; partial remission, 67.9%). Median time to progression was 841 days (range, 28 to 1,146 days). The most frequently reported grade 3/4 toxicity was myelosuppression. WHO grade 3/4 hematological toxicities included granulocytopenia (32.1%), anemia (9.9%), and thrombocytopenia (4.9%). Gastrointestinal toxicity was more common with the oral formulation than with IV fludarabine phosphate, but was generally mild to moderate and did not require treatment. Statistically significant improvements in mean emotional and insomnia quality-of-life scores were seen after treatment. Conclusion This study demonstrates that oral fludarabine phosphate is clinically effective and generally well tolerated by patients with previously untreated B-cell chronic lymphocytic leukemia. Oral fludarabine phosphate has a similar clinical efficacy and safety profile to the IV formulation. Oral fludarabine phosphate does not adversely affect quality of life and may improve emotional and insomnia scores.
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Horwitz, Mitchell E., Stephen Wease, Beth Blackwell, David Valcarcel, Francesco Frassoni, Jaap Jan Boelens, Stefan Nierkens, et al. "Phase I/II Study of Stem-Cell Transplantation Using a Single Cord Blood Unit Expanded Ex Vivo With Nicotinamide." Journal of Clinical Oncology 37, no. 5 (February 10, 2019): 367–74. http://dx.doi.org/10.1200/jco.18.00053.
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Purpose Increasing the number of hematopoietic stem and progenitor cells within an umbilical cord blood (UCB) graft shortens the time to hematopoietic recovery after UCB transplantation. In this study, we assessed the safety and efficacy of a UCB graft that was expanded ex vivo in the presence of nicotinamide and transplanted after myeloablative conditioning as a stand-alone hematopoietic stem-cell graft. Methods Thirty-six patients with hematologic malignancies underwent transplantation at 11 sites. Results The cumulative incidence of neutrophil engraftment at day 42 was 94%. Two patients experienced secondary graft failure attributable to viral infections. Hematopoietic recovery was compared with that observed in recipients of standard UCB transplantation as reported to the Center for International Blood and Marrow Transplant Research (n = 146). The median time to neutrophil recovery was 11.5 days (95% CI, 9 to 14 days) for recipients of nicotinamide-expanded UCB and 21 days (95% CI, 20 to 23 days) for the comparator ( P < .001). The median time to platelet recovery was 34 days (95% CI, 32 to 42 days) and 46 days (95% CI, 42 to 50 days) for the expanded and the comparator cohorts, respectively ( P < .001). The cumulative incidence of grade 2 to 4 acute graft-versus-host disease (GVHD) at day 100 was 44%, and grade 3 and 4 acute GVHD at day 100 was 11%. The cumulative incidence at 2 years of all chronic GVHD was 40%, and moderate/severe chronic GVHD was 10%. The 2-year cumulative incidences of nonrelapse mortality and relapse were 24% and 33%, respectively. The 2-year probabilities of overall and disease-free survival were 51% and 43%, respectively. Conclusion UCB expanded ex vivo with nicotinamide shortens median neutrophil recovery by 9.5 days (95% CI, 7 to 12 days) and median platelet recovery by 12 days (95% CI, 3 to 16.5 days). This trial establishes feasibility, safety, and efficacy of an ex vivo expanded UCB unit as a stand-alone graft.
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Gore, M., P. Mainwaring, R. A'Hern, V. MacFarlane, M. Slevin, P. Harper, R. Osborne, et al. "Randomized trial of dose-intensity with single-agent carboplatin in patients with epithelial ovarian cancer. London Gynaecological Oncology Group." Journal of Clinical Oncology 16, no. 7 (July 1998): 2426–34. http://dx.doi.org/10.1200/jco.1998.16.7.2426.
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PURPOSE We have examined the role of an increase in cisplatin dose-intensity in patients with advanced epithelial ovarian cancer by means of single-agent carboplatin therapy. PATIENTS AND METHODS Two hundred twenty-seven patients were randomized to treatment and eligible for analysis. The dose of carboplatin was calculated according to the Calvert formula. One hundred seventeen patients received carboplatin at an area under the concentration time curve (AUC) of 6 for six courses, administered every 28 days, and 110 patients received carboplatin at an AUC of 12 for four courses, administered every 28 days. Patients were eligible provided they had not received prior chemotherapy or radiotherapy and had International Federation of Gynecology and Obstetrics stages II to IV or relapsed stage I epithelial ovarian cancer. RESULTS The planned total-dose increase was 33% for the patients treated with carboplatin AUC 12, but the received percentage total-dose increase was 20%. There were no differences in progression-free or overall survival between the two treatment arms; the overall survival rate at 5 years was 31% and 34% of patients treated at AUCs 6 and 12, respectively. There was significantly more toxicity associated with carboplatin AUC 12, which resulted in more treatment delays and/or dose reductions (52% v 18%; P < .001). CONCLUSION We have shown that carboplatin can be delivered at an AUC of 12 for four courses without granulocyte colony-stimulating factor support, although significant hematologic toxicity occurs. Nonhematologic toxicities were not clinically significant. Carboplatin offers an opportunity to intensify cisplatin therapy, but a greater than two-fold increase in dose-intensity probably needs to be achieved before significant effects on survival will be produced and hematologic support will be required.
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Santoro, A., J. Voglova, N. Gabrail, T. Ciuleanu, M. Liberati, B. W. Hancock, S. Stromatt, and D. Caballero. "Comparative trial of BBR 2778 (pixantrone) + rituximab vs single agent rituximab in the treatment of relapsed/refractory indolent non-Hodgkin’s lymphoma (NHL)." Journal of Clinical Oncology 24, no. 18_suppl (June 20, 2006): 7578. http://dx.doi.org/10.1200/jco.2006.24.18_suppl.7578.
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7578 Background: BBR 2778 is a novel aza-anthracenedione that shows structural similarities to the anthracyclines, demonstrates single agent activity in patients with NHL, and does not exhibit cardiotoxic effects in animal models. This phase III open-label study was designed to compare the efficacy and tolerability of combination rituximab and BBR 2778, with that of single agent rituximab, in patients (pts) with relapsed or refractory indolent NHL. Methods: Pts were randomly assigned to receive both rituximab and BBR 2778 (experimental arm), or rituximab alone (control arm). In the experimental arm, pts received 375 mg/m2 rituximab IV on days 1 and 8 of cycles 1 and 2 only, and 90 mg/m2 BBR 2778 IV on days 2 and 8 of cycle 1, and on days 1 and 8 of all subsequent cycles. Pts could receive six 21-day cycles of BBR 2778. In the control arm, pts received 375 mg/m2 rituximab IV on days 1, 8 and 15 of cycle 1 and day 1 of cycle 2 only. Disease response was assessed every other cycle according to International Workshop to Standardize Response Criteria for NHL. Toxicities were assessed throughout the study using NCI-CTC criteria. Study was closed early due to poor enrollment. Results: 38 pts (20 experimental, 18 control) were enrolled. Mean age was 66 and 59 years in the experimental and control arm, respectively. Most patients were males and most had ECOG performance status 0 or 1. Efficacy is summarized in the table. Response rate (75 vs 33%) and time to progression (13.2 vs 8.1 months) were better in the BBR 2778 arm. Only pts in the experimental arm had study drug related serious adverse events (2 febrile neutropenia, 1 pneumonia, 1 neutropenia) and adverse events resulting in withdrawal (6 vs 0). Conclusions: Combination of BBR 2778 and rituximab is superior to rituximab alone with regard to time to progression and overall response rate. BBR 2778 combined with rituximab appeared to be a generally well tolerated regimen in patients with relapsed/refractory indolent NHL. [Table: see text] [Table: see text]
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Petrucci, Maria Teresa, Igor W. Blau, Paolo Corradini, Meletios A. Dimopoulos, Johannes Drach, Pilar Giraldo, Adriana Teixeira, and Joan Blade. "Efficacy and Safety of Re-Treatment with Bortezomib (Velcade©) in Patients with Multiple Myeloma: Results from a Prospective International Phase II Trial." Blood 112, no. 11 (November 16, 2008): 3690. http://dx.doi.org/10.1182/blood.v112.11.3690.3690.
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Abstract Background: Bortezomib has been shown to be effective in the treatment of multiple myeloma (MM). However, the data on response to re-treatment with bortezomib is very limited, mostly coming from small retrospective studies. Response to re-treatment is particularly relevant in patients with relapsing incurable conditions such as MM. The primary objective of this first international prospective phase II trial was to determine the best response to bortezomib re-treatment in patients with MM. Secondary objectives included safety profile, duration of response, time to progression, best M protein response and the evaluation of the best investigator-assessed response compared to the best response reported to the previous bortezomib treatment. Methods: Patients with secretory MM were eligible if they had responded (CR or PR) to a bortezomib-based most recent treatment and had a treatment-free interval of at least 6 months since the last bortezomib dose. They needed to meet the PD criteria as defined by European Group for Blood and Marrow Transplantation (EBMT). Patients received bortezomib starting at the last tolerated dose in the previous bortezomib regimen (1.3 or 1.0 mg/m2). Bortezomib was administered alone or in combination with dexamethasone at investigator discretion. Bortezomib was administered as an intravenous injection on days 1, 4, 8 and 11 of a 21-day cycle up to a maximum of 8 cycles. Response was evaluated every 6 weeks according to EBMT criteria. Adverse events (AEs) were assessed from informed consent until at least 30 days after treatment and were graded by the NCI-CTCAE. This clinical trial closed to recruitment on 30th June 2008 after reaching the planned sample size of 128 patients, with 57 patients still receiving treatment. The results presented include the efficacy and safety data available for 100 patients who had completed at least 2 treatment cycles at the time of data cut-off (16 July 2008) or who had withdrawn from therapy for any reason. Results: The 100 patients (M: 59, F: 41; median age 66 years) who received at least 1 dose of bortezomib are included in the current safety analysis. The median time from diagnosis of MM was 4.5 years (range 0–14 years) and 59% had received 3 or more lines of prior therapy (including the previous bortezomib therapy). Karnofsky performance status was £ 70% in 16% of patients. Twenty-six percent of patients had achieved a complete response (CR) with the last bortezomib regimen. The median treatment free interval since the previous bortezomib treatment was 14.3 months. Eighty-seven percent of the patients received at least 3 cycles and the median number of completed cycles was 5 cycles. Dexamethasone was added to the bortezomib treatment in 69% of patients. In the 97 patients eligible for the current efficacy analysis, the overall response rate (ORR) by EBMT criteria [CR+PR] was 26.8% (CI=18.3– 36.8), with 3.1% complete responses, whilst ORR + minimal response (MR) was 46.4%. The ORR did not differ in patients treated with bortezomib plus dexamethasone (27.9%, CI=17.7– 40.1) versus those treated with bortezomib alone (24.1%, CI=10.3–43.5). The median time to at least PR was 43 days, with a median time to best response of 64 days. The most commonly reported related grade 3/4 adverse events were thrombocytopenia (24%), neutropenia (5%) and diarrhea (5%). Peripheral neuropathy (PN) was observed in 20% of patients, with grade 3 PN reported in 6% of patients only. Serious TEAE’s were reported in 23% of patients and 10% of patients discontinued bortezomib due to related TEAE’s including 6 cases of PN. TEAE’s leading to death were reported in three patients. Conclusions: Response after re-treatment with bortezomib alone or in combination with dexamethasone in heavily pre-treated multiple myeloma patients was still high, and the adverse event profile was consistent with the already known safety profile. Updated results will be presented at time of the meeting.
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Mouncey, Paul R., Tiffany M. Osborn, G. Sarah Power, David A. Harrison, M. Zia Sadique, Richard D. Grieve, Rahi Jahan, et al. "Protocolised Management In Sepsis (ProMISe): a multicentre randomised controlled trial of the clinical effectiveness and cost-effectiveness of early, goal-directed, protocolised resuscitation for emerging septic shock." Health Technology Assessment 19, no. 97 (November 2015): 1–150. http://dx.doi.org/10.3310/hta19970.
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BackgroundEarly goal-directed therapy (EGDT) is recommended in international guidance for the resuscitation of patients presenting with early septic shock. However, adoption has been limited and uncertainty remains over its clinical effectiveness and cost-effectiveness.ObjectivesThe primary objective was to estimate the effect of EGDT compared with usual resuscitation on mortality at 90 days following randomisation and on incremental cost-effectiveness at 1 year. The secondary objectives were to compare EGDT with usual resuscitation for requirement for, and duration of, critical care unit organ support; length of stay in the emergency department (ED), critical care unit and acute hospital; health-related quality of life, resource use and costs at 90 days and at 1 year; all-cause mortality at 28 days, at acute hospital discharge and at 1 year; and estimated lifetime incremental cost-effectiveness.DesignA pragmatic, open, multicentre, parallel-group randomised controlled trial with an integrated economic evaluation.SettingFifty-six NHS hospitals in England.ParticipantsA total of 1260 patients who presented at EDs with septic shock.InterventionsEGDT (n = 630) or usual resuscitation (n = 630). Patients were randomly allocated 1 : 1.Main outcome measuresAll-cause mortality at 90 days after randomisation and incremental net benefit (at £20,000 per quality-adjusted life-year) at 1 year.ResultsFollowing withdrawals, data on 1243 (EGDT,n = 623; usual resuscitation,n = 620) patients were included in the analysis. By 90 days, 184 (29.5%) in the EGDT and 181 (29.2%) patients in the usual-resuscitation group had died [p = 0.90; absolute risk reduction −0.3%, 95% confidence interval (CI) −5.4 to 4.7; relative risk 1.01, 95% CI 0.85 to 1.20]. Treatment intensity was greater for the EGDT group, indicated by the increased use of intravenous fluids, vasoactive drugs and red blood cell transfusions. Increased treatment intensity was reflected by significantly higher Sequential Organ Failure Assessment scores and more advanced cardiovascular support days in critical care for the EGDT group. At 1 year, the incremental net benefit for EGDT versus usual resuscitation was negative at −£725 (95% CI −£3000 to £1550). The probability that EGDT was more cost-effective than usual resuscitation was below 30%. There were no significant differences in any other secondary outcomes, including health-related quality of life, or adverse events.LimitationsRecruitment was lower at weekends and out of hours. The intervention could not be blinded.ConclusionsThere was no significant difference in all-cause mortality at 90 days for EGDT compared with usual resuscitation among adults identified with early septic shock presenting to EDs in England. On average, costs were higher in the EGDT group than in the usual-resuscitation group while quality-adjusted life-years were similar in both groups; the probability that it is cost-effective is < 30%.Future workThe ProMISe (Protocolised Management In Sepsis) trial completes the planned trio of evaluations of EGDT across the USA, Australasia and England; all have indicated that EGDT is not superior to usual resuscitation. Recognising that each of the three individual, large trials has limited power for evaluating potentially important subgroups, the harmonised approach adopted provides the opportunity to conduct an individual patient data meta-analysis, enhancing both knowledge and generalisability.Trial registrationCurrent Controlled Trials ISRCTN36307479.FundingThis project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full inHealth Technology Assessment; Vol. 19, No. 97. See the NIHR Journals Library website for further project information.
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Hijas-Gómez, Ana Isabel, Mar Polo-DeSantos, Setefilla Luengo-Matos, and Luis María Sánchez-Gómez. "PP107 Harpoon™: A Novel Device For Transapical Mitral Valve Repair." International Journal of Technology Assessment in Health Care 35, S1 (2019): 57–58. http://dx.doi.org/10.1017/s026646231900237x.
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IntroductionMitral regurgitation (MR) is the most prevalent heart valve condition in Western countries. Open-heart mitral valve reconstruction is the conventional surgical treatment for MR, whereby the valve's cords are replaced with expanded polytetrafluoroethylene cords. Novel devices have introduced minimally invasive alternatives, such as transapical beating-heart valve repair. Among these alternatives, the Harpoon™ Mitral Valve Repair System (Edwards Lifesciences LLC) may have potential advantages (a smaller diameter valve introducer to minimize bleeding and a different anchoring mechanism). This study aimed to assess the efficacy and safety of Harpoon in minimally invasive mitral valve surgery.MethodsAn early assessment of the technology was conducted by reviewing relevant literature from the following databases: PubMed, EMBASE, Web of Science, the Trip Database, the International Clinical Trials Registry Platform, ClinicalTrials.gov, the Cochrane Library, and the Centre for Reviews and Dissemination. Relevant clinical studies published up to 30 January 2018 were included.ResultsOnly two publications, by the same research group, were included: an observational study of 11 patients and the prospective, nonrandomized TRACER trial (n = 30). During the procedure, MR was reduced from severe to none in 73 to 86 percent of patients and severe to mild in 14 to 27 percent. At one month, MR was rated as mild or lower in 82 to 89 percent of patients. At six months, MR had worsened to moderate or severe in 16 percent of patients from the TRACER trial. Safety issues within 30 days (18% to 27% of patients) included intraoperative conversion to open surgery, reoperation, pleural effusion, hemopericardium, and atrial fibrillation. There were no intra- or postoperative deaths.ConclusionsCurrent evidence on the Harpoon device is scarce. Although published studies showed improvement in MR in most patients, there are still issues regarding safety, lack of long-term results, comparability with other procedures, and costs. While promising, further research is required before recommending routine use of this technology.
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Pople, Ian, Wai Poon, Richard Assaker, David Mathieu, Mark Iantosca, Ernest Wang, Li Wei Zhang, et al. "Comparison of Infection Rate With the Use of Antibiotic-Impregnated vs Standard Extraventricular Drainage Devices." Neurosurgery 71, no. 1 (March 13, 2012): 6–13. http://dx.doi.org/10.1227/neu.0b013e3182544e31.
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Abstract BACKGROUND: External ventricular drainage (EVD) catheters provide reliable and accurate means of monitoring intracranial pressure and alleviating elevated pressures via drainage of cerebrospinal fluid (CSF). CSF infections occur in approximately 9% of patients. Antibiotic-impregnated (AI) EVD catheters were developed with the goal of reducing the occurrence of EVD catheter-related CSF infections and their associated complications. OBJECTIVE: To present an international, prospective, randomized, open-label trial to evaluate infection incidence of AI vs standard EVD catheters. METHODS: Infection was defined as (1) proven infection, positive CSF culture and positive Gram stain or (2) suspected infection: (A) positive CSF culture with no organisms identified on initial Gram stain; (B) negative CSF culture with a gram-positive or -negative stain; (C) CSF leukocytosis with a white blood cell/red blood cell count >0.02. RESULTS: Four hundred thirty-four patients underwent implantation of an EVD catheter. One hundred seventy-six patients in the AI-EVD cohort and 181 in the standard EVD catheter cohort were eligible for evaluation of infection. The 2 groups were similar in all clinical characteristics. Proven infection was documented in 9 (2.5%) patients (AI: 4 [2.3%] vs standard: 5 [2.8%], P = 1.0). Suspected infection was documented in 31 (17.6%) patients receiving AI and 37 (20.4%) patients receiving standard EVD catheters, P = .504. Duration of time to suspected infection was prolonged in the AI cohort (8.8 ± 6.1 days) compared with the standard EVD cohort (4.6 ± 4.2 days), P = .002. CONCLUSION: AI-EVD catheters were associated with an extremely low rate of catheter-related infections. AI catheters were not associated with risk reduction in EVD infection compared to standard catheters. Use of AI-EVD catheters is a safe option for a wide variety of patients requiring CSF drainage and monitoring, but the efficacy of AI-EVD catheters was not supported in this trial.
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Trappe, Ralf Ulrich, Christian Koenecke, Martin H. Dreyling, Christiane Pott, Ulrich Duehrsen, Norbert Meidenbauer, Dennis Hahn, et al. "Treatment stratification in B-cell PTLD after solid organ transplantation (SOT) by international prognostic index (IPI) and response to rituximab: Interim results from the PTLD-2 trial." Journal of Clinical Oncology 38, no. 15_suppl (May 20, 2020): 8045. http://dx.doi.org/10.1200/jco.2020.38.15_suppl.8045.
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8045 Background: The PTLD-1 trials have established risk-stratified sequential treatment of B-cell PTLD. After rituximab induction, patients (pts) in complete remission (25 %) received rituximab consolidation, while all others received R-CHOP. The PTLD-2 trial tests modified risk-stratification including clinical risk factors. These are the results of the 2nd scheduled interim analysis (40/60 planned pts). Methods: The prospective, multicenter phase II PTLD-2 trial (NCT02042391) enrols treatment-naïve adult SOT recipients with CD20-positive PTLD. Key exclusion criteria are CNS involvement, ECOG > 2, pregnancy, and severe organ dysfunction or severe, active infection. Treatment consists of rituximab (1400 mg SC; first application 375 mg/m2 IV) on days 1, 8, 15 and 22. After restaging, pts in CR as well as those in PR with ≤ 2 IPI risk factors at diagnosis (low-risk group) continue with four three-weekly courses of rituximab. Most other pts (high-risk group) receive 4 cycles of R-CHOP-21, while thoracic SOT recipients who progress under rituximab (very-high-risk group) receive six cycles of alternating R-CHOP-21 and R-DHAOx. The primary endpoint (event-free survival in the low-risk group) is not analyzed here. Secondary endpoints presented here are response and overall response (ORR) by computed tomography, overall survival (OS), time to progression (TTP) and treatment-related mortality (TRM) overall and by risk group. Results: 40 pts were recruited at 12 centers (2015 – 2019). 21/40 were kidney, 11 lung, 4 liver, 3 heart, and 1 liver/kidney transplant recipients. Median age was 54 years. 38/40 PTLD were monomorphic and 15/40 EBV-associated. 38 pts were evaluated for response at interim staging: 13 were allocated to the low-risk, 17 to the high-risk and 8 to the very-high-risk group. ORR was 28/30 (93 %, CR: 16/30 [53 %]). With a median follow-up of 1.9 years, the 1-year/3-year Kaplan-Meier (KM) estimates of TTP and OS in the intention-to-treat population (40 pts) were 85 %/80 % and 70 %/70 %, respectively. In the low-risk group, the 2-year KM estimate of OS was 100 %. The frequency of infections (all grades) was 50 %, and TRM occurred in 3/40 pts (8 %). Conclusions: One third of enrolled pts were treated in the low-risk group and the recruitment goal for evaluation of the primary endpoint will likely be reached. Interim efficacy and toxicity data with rituximab SC and modified risk-stratification are encouraging despite the inclusion of 35 % thoracic SOT recipients. Clinical trial information: NCT02042391 .
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Weiss, Emmanuel, Jean-Ralph Zahar, Jeff Alder, Karim Asehnoune, Matteo Bassetti, Marc J. M. Bonten, Jean Chastre, et al. "Elaboration of Consensus Clinical Endpoints to Evaluate Antimicrobial Treatment Efficacy in Future Hospital-acquired/Ventilator-associated Bacterial Pneumonia Clinical Trials." Clinical Infectious Diseases 69, no. 11 (February 4, 2019): 1912–18. http://dx.doi.org/10.1093/cid/ciz093.
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Abstract Background Randomized clinical trials (RCTs) in hospital-acquired and ventilator-associated bacterial pneumonia (HABP and VABP, respectively) are important for the evaluation of new antimicrobials. However, the heterogeneity in endpoints used in RCTs evaluating treatment of HABP/VABP may puzzle clinicians. The aim of this work was to reach a consensus on clinical endpoints to consider in future clinical trials evaluating antimicrobial treatment efficacy for HABP/VABP. Methods Twenty-six international experts from intensive care, infectious diseases, and the pharmaceutical industry were polled using the Delphi method. Results The panel recommended a hierarchical composite endpoint including, by priority order, (1) survival at day 28, (2) mechanical ventilation–free days through day 28, and (3) clinical cure between study days 7 and 10 for VABP; and (1) survival (day 28) and (2) clinical cure (days 7–10) for HABP. Clinical cure was defined as the combination of resolution of signs and symptoms present at enrollment and improvement or lack of progression of radiological signs. More than 70% of the experts agreed to assess survival and mechanical ventilation–free days though day 28, and clinical cure between day 7 and day 10 after treatment initiation. Finally, the hierarchical order of endpoint components was reached after 3 Delphi rounds (72% agreement). Conclusions We provide a multinational expert consensus on separate hierarchical composite endpoints for VABP and HABP, and on a definition of clinical cure that could be considered for use in future HABP/VABP clinical trials.
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Beyer-Westendorf, Jan, Sandra Marten, Luise Tittl, Christiane Naue, and Martin Bornhäuser. "Venous Thromboembolism Therapy with Apixaban in Daily Care Patients: Results from the Dresden NOAC Registry." TH Open 05, no. 02 (April 2021): e143-e151. http://dx.doi.org/10.1055/s-0041-1728675.
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AbstractThe effectiveness and safety of venous thromboembolism (VTE) treatment with apixaban, demonstrated in phase III trials, need to be confirmed in daily care.Using data from the prospective, noninterventional cross-indication Dresden NOAC Registry we evaluated rates of VTE recurrence and bleeding complications during apixaban treatment of VTE patients. For this analysis, we only included patients with acute VTE who started apixaban within 14 days after diagnosis and who were enrolled within these 14 days. Patient characteristics, treatment persistence, and clinical outcomes were assessed.Between August 1st, 2014 and October 31, 2018, 352 patients with apixaban treatment for acute VTE were enrolled. During treatment (median exposure 13.7 ± 9.8 months; median follow-up 21.7 ± 6.1 months) rates of recurrent VTE and International Society on Thrombosis and Haemostasis major bleeding were 1.3/100 pt.years (95% confidence interval or CI 0.4–3.0) and 1.5/100 pt.years (0.6–3.3), respectively. At 6 months. 68.6% of patients were still taking apixaban, 23.9% had a scheduled end of treatment, 6.3% were switched to other anticoagulants, and the remaining 2.3% had unplanned complete discontinuation of anticoagulation.Of the 188 patients stopping apixaban, 12 (6.4%) experienced a recurrent VTE (six pulmonary embolisms ± deep vein thrombosis, six deep vein thrombosis; mean time between stopping anticoagulation and VTE recurrence 5.2 ± 4.1 months [range 14–417 days]).Our findings suggest that, in daily care, apixaban demonstrated high effectiveness, safety, and persistence in the treatment of acute VTE with low rates of unplanned discontinuation.
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Christian, Beth, Anne Kopko, Todd A. Fehniger, Nancy L. Bartlett, and Kristie A. Blum. "A Phase I Trial of the Histone Deacetylase (HDAC) Inhibitor, Panobinostat, in Combination with Lenalidomide in Patients with Relapsed/Refractory Hodgkin's Lymphoma (HL)." Blood 120, no. 21 (November 16, 2012): 1644. http://dx.doi.org/10.1182/blood.v120.21.1644.1644.
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Abstract Abstract 1644 Introduction: Previous phase 2 single agent trials with the immunomodulatory agent, lenalidomide, in patients with relapsed or refractory HL demonstrated overall response rates (ORR) of 14–29%, with a median duration of response of 6 months. Likewise, a single agent trial utilizing the orally available HDAC inhibitor, panobinostat, in 127 patients with relapsed/refractory HL after prior autologous stem cell transplant (ASCT) demonstrated an ORR of 27% with a median duration of response of 6.9 months. Based on the encouraging single agent activity of these agents and in vitro synergy of combined panobinostat and lenalidomide in myeloma cell lines, we are conducting a phase I/II trial to determine the dose limiting toxicity (DLT), maximum tolerated dose (MTD), and overall response rate (ORR) with this combination and results of the phase I study are presented. Methods: Patients with relapsed or refractory classical HL (cHL) or lymphocyte predominant HL (LP HL) after at least one prior therapy are eligibile. Measurable disease ≥1 cm in at least one dimension, ejection fraction ≥45%, ECOG PS 0–2, QTc on ECG ≤ 450 msec, ANC ≥1200/mm3, platelets ≥100,000/mm3, AST/ALT ≤ 2.5 × the upper limit of normal (ULN), bilirubin ≤ 1.5 × ULN, and creatinine clearance ≥60 ml/min are required at study entry. Prior ASCT, lenalidomide, and panobinostat are permitted. In the phase I trial, escalating doses of panobinostat (15 or 20 mg) days 1, 3, and 5 weekly are combined with lenalidomide 25 mg days 1–21 utilizing a cohorts of 3 design. DLT is defined during cycle 1 and includes grade 4 neutropenia or thrombocytopenia, grade 4 infection, grade 3 infection for > 7 days, treatment delays > 14 days, and other grade 3–4 non-hematologic toxicity. Six patients will be enrolled at the MTD to ensure patient safety prior to phase 2 enrollment. Twenty-eight days defines a cycle and patients may remain on therapy until disease progression or unacceptable toxicity. Response is assessed after cycles 2, 6, and every 4 cycles thereafter by International Harmonization Criteria (Cheson, JCO 2007). Results: Seven patients (6 males) with cHL (n=6) and LP HL (n=1) and a median age of 31 (range 24–72) have been enrolled. Patients received a median of 3 prior therapies (range 3–5), 1 patient received prior radiotherapy, 3 patients were refractory to their most recent therapy, 3 patients had prior ASCT, 6 patients had received prior brentuximab vedotin, and no patients had prior lenalidomide or panobinostat. Other characteristics included stage III-IV disease in 100% (57% stage IV), bulky adenopathy ≥5 cm in 14%, and bone marrow involvement in 14%. Seven patients have completed one or more cycles of therapy (median 3, range 1–4) with either 15 mg (n=3) or 20 mg (n=4) of panobinostat + 25 mg lenalidomide. Four patients discontinued therapy for progressive disease (PD) after 4 cycles (n=3) and 1 cycle (n=1), respectively. Three patients continue to receive protocol treatment, all receiving panobinostat 20 mg days 1, 3, and 5 weekly. No DLTs have been observed. Grade 3–4 events included neutropenia (43%), lymphopenia (29%), thrombocytopenia (29%), and hypophosphatemia (29%). No QTc prolongation has been observed. Dose reductions from 15 mg panobinostat days 1, 3, and 5 weekly + lenalidomide 25 mg to 15 mg panobinostat days 1, 3, and 5 weeks 1 and 3 only + 20 mg lenalidomide were required in 2 patients for grade 3–4 neutropenia during cycles 3 and 4. ORR is 33% in 6 evaluable patients with a complete response in 1 patient with cHL and partial response in 1 patient with LP HL. One patient has not yet undergone restaging scans. Conclusions: Combined panobinostat and lenalidomide appears to be well tolerated in patients with relapsed/refractory HL without dose limiting myelosuppression, cardiac toxicity, QTc prolongation, or other grade 3–4 non-hematologic toxicity. Study accrual continues, 2 additional patients will be added to the highest dose level (panobinostat 20 mg days 1, 3, and 5 weekly for 4 weeks + lenalidomide 25 mg days 1–21) to complete the phase I trial and will be followed by anticipated enrollment of a maximum of 25 patients to a two-stage phase 2 trial targeting an ORR of 30% or higher. Disclosures: Blum: Celgene: Research Funding; Novartis: Research Funding. Off Label Use: Panobinostat and lenalidomide are not approved for the treatment of HL.
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Wu, Shou-Bao, Elena Volodicheva, Olga Vinogradova, Today Su, Howard Cheng, Pei-Ni Chen, and Shin-Shiou Lin. "The potential treatment of antroquinonol in adult patients with relapsed acute myeloid leukemia (AML)." Journal of Clinical Oncology 39, no. 15_suppl (May 20, 2021): e19001-e19001. http://dx.doi.org/10.1200/jco.2021.39.15_suppl.e19001.
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e19001 Background: The prognosis of relapsed acute myeloid leukemia (R/R AML) remains poor and the management is challenging. Despite the increasing availability of targeted agents, the lower responses still represent a major obstacle to overcome. Antroquinonol is an isoprenyltransferase inhibitor with antitumor activity in vitro and xenograft models of AML. Our aim is to evaluate hematopoietic recovery with Antroquinonol in this phase IIa study. Here, the results from our phase IIa trial demonstrate the safety, tolerability, and activity of Antroquinonol in patients with relapsed AML. Methods: GHAML-2-001 is a phase IIa, open-label study in adult patients with relapsed acute myeloid leukemia or at initial diagnosis when no intensive treatment is possible. Antroquinonol 200 mg BID was administered in a 28-day cycle (up to six cycles). The primary endpoint is hematologic response rate. Secondary endpoints consist of 4-week survival, 24-week survival, duration of hematologic response and transfusion independence, and the response rates. Therapy was continued for as long as tolerated and there was continuing evidence of therapeutic benefit in the opinion of the investigator. Treatment response was assessed by the International Working Group (IWG) response criteria after each cycle. Results: Twelve eligible patients had a median age of 62.5 years (range, 42-69; 6 males, 6 females) and the whole process was conducted between March 2019 and February 2020. Of the two patients who did not complete the therapy period were due to the patient's decision to withdraw: One patient withdrew on day 7 and the other one withdrew on day 49. Among other ten patients who finished all six cycles (168 days), Antroquinonol showed excellent safety and favorable tolerability. At the end of the treatment, the rate of complete remission (CR/CRi) after 6-completed cycles was 50% (5/10) and the 24-week survival rate was 100%. Transfusion independence was achieved in 8 (80%) of 10 transfusion independence evaluable patients at the end of the 6th cycle treatment. Conclusions: In high-risk relapsed AML patients, orally administered Antroquinonol induced CRs and was well tolerated. This significant result suggests the potential of Antroquinonol for the therapy of this underserved population. Clinical trial information: NCT03823352. Clinical trial information: NCT03823352.
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Zheng, Rong, Congfei Wang, Xiaoxue Huang, Qingliang Lin, Daxin Huang, Xiao-Bo Li, Heguang Huang, and Benhua Xu. "Chemotherapy-based split stereotactic body radiation therapy for borderline resectable and locally advanced pancreatic cancer: study protocol of a prospective, single-arm phase II trial." BMJ Open 10, no. 11 (November 2020): e039900. http://dx.doi.org/10.1136/bmjopen-2020-039900.
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IntroductionThe question of how to administer adequate chemotherapy to synchronise stereotactic body radiation therapy (SBRT) treatment strategy to maximise the benefits of neoadjuvant therapy for the improved prognosis of patients with borderline resectable (BRPC) and locally advanced (LAPC) pancreatic cancer is a challenging and debatable issue. No studies have yet evaluated the efficacy of split-course SBRT as the neoadjuvant chemoradiotherapy regimen. We aimed to study whether neoadjuvant chemotherapy plus split-course SBRT results in better outcomes in BRPC and LAPC patients.Methods and analysisTreatment-naïve patients with radiographically confirmed BRPC or LAPC, supporting biopsy results and no severe comorbidities will be enrolled. They will be treated with nab-paclitaxel plus gemcitabine (nab-P+Gem) chemotherapy plus split-course SBRT, followed by an investigator’s choice of continuation of treatment with nab-P+Gem or surgery. nab-P+Gem chemotherapy will commence on day 1 for each of six cycles: nab-paclitaxel 125 mg/m2 intravenous infusion over approximately 30–45 min, followed by gemcitabine 1000 mg/m2 intravenous infusion over about 30 min on days 1 and 15 of each 28-day cycle. During the first and second cycles of chemotherapy, SBRT will be given as a single irradiation of 10 Gy four times (days 2 and 16 of each 28-day cycle). The primary endpoint is progression-free survival; while the secondary outcomes are the time to treatment failure, disease control rate, overall response rate, overall survival, R0 resection rate and incidence of adverse effects.Ethics and disseminationThe study protocol was approved by the Ethics Committee of Xiehe Affiliated Hospital of Fujian Medical University (No. 2019YF015-01). Results from our study will be disseminated in international peer-reviewed journals. All study procedures were developed in order to assure data protection and confidentiality.Trial registration numberNCT04289792.
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Auer, Rebecca L., Roger G. Owen, Shirley D'Sa, Guy Pratt, Bilyana Popova, Laura Clifton Hadley, Oliver Schofield, Nicholas Counsell, and Paul Smith. "R2W: Subcutaneous Bortezomib, Cyclophosphamide and Rituximab (BCR) Versus Fludarabine, Cyclophosphamide and Rituximab (FCR) for Initial Therapy of WaldenstrőM's Macroglobulinemia: A Randomised Phase II Study." Blood 128, no. 22 (December 2, 2016): 618. http://dx.doi.org/10.1182/blood.v128.22.618.618.
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Abstract Introduction Earlier studies have indicated that the combination of bortezomib and rituximab is highly active in Waldenstrőm's macroglobulinemia (WM). However, there is scope to improve the complete response rate, duration of response and toxicity profile. We evaluated the efficacy and tolerability of the addition of cyclophosphamide to bortezomib and rituximab in previously untreated patients with WM. Methods Symptomatic treatment-naïve patients were enrolled into this prospective randomised (2:1), multicentre, non-comparative Phase II study (NCT01592981). Patients were stratified according to the International Prognostic Scoring System for WM. Patients were treated with BCR (Bortezomib 1.6 mg/m2 s.c. days 1, 8, 15; Cyclophosphamide 250 mg/m2 oral days 1, 8, 15; Rituximab 375mg/m2 i.v. days 1, 8, 15, 22 cycles 2 and 5 only) or FCR (Fludarabine 40mg/m2 oral days 1-3; Cyclophosphamide 250 mg/m2 oral days 1-3; Rituximab 375mg/m2i.v. days 1, 8, 15, 22 cycles 2 and 5 only) for 6 cycles repeated every 28 days. Rituximab and bortezomib were provided free of charge by Roche and Janssen, respectively. The primary endpoint was investigator assessed overall response rate (ORR) using consensus criteria. Results Sixty patients were enrolled into this study and 59 received trial treatment (BCR=42, FCR=17). Of all registered patients, 73% were male, median (range) age was 67 years (43-87), Haemoglobin 9.8 g/dL (6.5-14.0), serum IgM paraprotein 34 g/L (3.2-80.2), plasma viscosity 3.6 mPa.s (2.0-9.3) and 25/30/45% were low/intermediate/high risk respectively. Six cycles were completed by 92.9% of BCR and 76.5% of FCR patients, one patient withdrew from the study prior to starting trial treatment. Dose reductions were needed in 38.1% of BCR and 52.9% of FCR patients and treatment delays occurred in 64.3% of BCR and 64.7% of FCR patients. ORR was 97.6% in BCR patients with 78.6% achieving a major response (CR=1, VGPR=8, PR=24, MR=7, SD=1), one patient was not assessed as no evidence of WM was found upon central review; 82.4% in FCR patients with a major response rate of 76.5% (CR=0, VGPR=3, PR=10, MR=1, SD=2), one patient stopped treatment after cycle 1 due to continuing cytopenia (grade 4). Responses were also evaluated in both marrow and peripheral blood using a disease specific multiparamater flow cytometric assay. After a median follow-up of 18 months, 54 patients were progression-free; 3 patients progressed (all BCR) and 3 patients died, 2 from myelodysplastic syndrome (MDS) (both FCR) and 1 from pneumonia (BCR). Grade 3 or higher toxicities included anemia (5 [11.9%] BCR; 3 [17.6%] FCR), neutropenia (11 [26.2%] BCR; 12 [70.6%] FCR), thrombocytopenia (7 [16.7%] BCR; 6 [35.3%] FCR) and infection (2 [4.8%] BCR; 5 [29.4%] FCR). No grade 3 or higher neuropathy was reported. Conclusions BCR and FCR are both highly effective treatments for primary therapy of WM but FCR is associated with increased toxicity and concerning incidence of secondary MDS. BCR warrants further investigation in a randomised Phase III trial. Continued follow-up of R2W patients is also important to provide reliable estimates for duration of response, progression-free survival and overall survival. Disclosures Auer: Janssen: Consultancy, Other: Drug provided for clinical trial; Bristol Myers Squibb: Consultancy. Owen:Janssen: Consultancy; Roche: Honoraria; Pharmacyclics: Consultancy.
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Ridolfi, Laura, Francesco de Rosa, Laura Fiammenghi, Massimiliano Petrini, Anna Maria Granato, Valentina Ancarani, Elena Pancisi, et al. "Complementary vaccination protocol with dendritic cells pulsed with autologous tumour lysate in patients with resected stage III or IV melanoma: protocol for a phase II randomised trial (ACDC Adjuvant Trial)." BMJ Open 8, no. 8 (August 2018): e021701. http://dx.doi.org/10.1136/bmjopen-2018-021701.
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IntroductionSurgery is one of the treatments of choice for patients with a single metastasis from melanoma but is rarely curative. Such patients could potentially benefit from consolidation immunotherapy. Vaccination with dendritic cells (DCs) loaded with tumour antigens elicits a tumour-specific immune response. In our experience, patients who developed delayed type hypersensitivity (DTH) after DC vaccination showed a median overall survival (OS) of 22.9 monthsvs4.8 months for DTH-negative cases. A phase II randomised trial showed an advantage OS of a DC vaccine over a tumour cell-based vaccine (2-year OS 72% vs31%, respectively). Given that there is no standard therapy after surgical resection of single metastases, we planned a study to compare vaccination with DCs pulsed with autologous tumour lysate versus follow-up.Methods and analysisThis is a randomised phase II trial in patients with resected stage III/IV melanoma. Assuming a median relapse-free survival (RFS) of 7.0 months for the standard group and 11.7 months for the experimental arm (HR 0.60), with a two-sided tailed alpha of 0.10, 60 patients per arm must be recruited. An interim futility analysis will be performed at 18 months. The DC vaccine, produced in accordance with Good Manufacturing Practice guidelines, consists of autologous DCs loaded with autologous tumour lysate and injected intradermally near lymph nodes. Vaccine doses will be administered every 4 weeks for six vaccinations and will be followed by 3 million unit /day of interleukin-2 for 5 days. Tumour restaging, blood sampling for immunological biomarkers and DTH testing will be performed every 12 weeks.Ethics and disseminationThe protocol, informed consent and accompanying material given to patients were submitted by the investigator to the Ethics Committee for review. The local Ethics Committee and the Italian Medicines Agency approved the protocol (EudraCT code no.2014-005123-27). Results will be published in a peer-reviewed international scientific journal.Trial registration number2014-005123-27.
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Pardanani, Animesh, Jason R. Gotlib, Catriona Jamieson, Jorge E. Cortes, Moshe Talpaz, Richard M. Stone, Michael H. Silverman, D. Gary Gilliland, Jolene Shorr, and Ayalew Tefferi. "Safety and Efficacy of TG101348, a Selective JAK2 Inhibitor, in Myelofibrosis." Journal of Clinical Oncology 29, no. 7 (March 1, 2011): 789–96. http://dx.doi.org/10.1200/jco.2010.32.8021.
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Purpose Myelofibrosis is a myeloid malignancy associated with anemia, splenomegaly, and constitutional symptoms. Patients frequently harbor JAK-STAT activating mutations that are sensitive to TG101348, a selective small-molecule Janus kinase 2 (JAK2) inhibitor. Patients and Methods In a multicenter phase I trial, oral TG101348 was administered once a day to patients with high- or intermediate-risk primary or post–polycythemia vera/essential thrombocythemia myelofibrosis. Results Fifty-nine patients were treated, including 28 in the dose-escalation phase. The maximum-tolerated dose was 680 mg/d, and dose-limiting toxicity was a reversible and asymptomatic increase in the serum amylase level. Forty-three patients (73%) continued treatment beyond six cycles; the median cumulative exposure to TG101348 was 380 days. Adverse events included nausea, vomiting, diarrhea, anemia, and thrombocytopenia; corresponding grades 3 to 4 incidence rates were 3%, 3%, 10%, 35%, and 24%. TG101348 treatment had modest effect on serum cytokine levels, but greater than half of the patients with early satiety, night sweats, fatigue, pruritus, and cough achieved rapid and durable improvement in these symptoms. By six and 12 cycles of treatment, 39% and 47% of patients, respectively, had achieved a spleen response per International Working Group criteria. The majority of patients with leukocytosis or thrombocytosis at baseline (n = 28 and n = 10, respectively) achieved normalization of blood counts after six (57% and 90%, respectively) and 12 (56% and 88%, respectively) cycles. A significant decrease in JAK2 V617F allele burden was observed at 6 months in mutation-positive patients (n = 51; P = .04), particularly in the subgroup with allele burden greater than 20% (n = 23; P < .01); the decrease was durable at 12 months. Conclusion TG101348 is well tolerated and produces significant reduction in disease burden and durable clinical benefit in patients with myelofibrosis.
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Scotch, Allison H., Robyn M. Scherber, Nan Zhang, Heidi E. Kosiorek, Amylou C. Dueck, Holly Geyer, Veena Fauble, et al. "Myeloproliferative Neoplasm Quality of Life (MPN-QOL) Study Group: Interim Results from the MPN Experimental Assessment of Symptoms By Utilizing Repetitive Evaluation (MEASURE) Trial." Blood 128, no. 22 (December 2, 2016): 5479. http://dx.doi.org/10.1182/blood.v128.22.5479.5479.
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Abstract Background: Myeloproliferative neoplasms (MPN) including polycythemia vera (PV), essential thrombocythemia (ET), and myelofibrosis (MF) are clonal hemopathies characterized by burdensome symptom profiles and impaired quality of life. Few studies have evaluated patient-reported outcomes during treatment with non-experimental pharmacological regimens. Aims: The Myeloproliferative Neoplasm Quality of Life (MPN-QOL) Study Group aims to objectively quantify MPN symptom severity, frequency and quality of life at baseline and throughout treatment with non-experimental therapies utilizing the Myeloproliferative Neoplasm Symptom Assessment Form - Total Symptom Score (MPN-SAF TSS; JCO 2012). In this abstract, we provide updated results for the prospective international cohort trial currently in active enrollment: the MPN Experimental Assessment of Symptoms by Utilizing Repetitive Evaluation (MEASURE) trial. Methods: This study aims to recruit 180 international ET, PV, and MF (including primary MF and post-ET or post-PV MF) patients receiving non-experimental medical therapy and/or phlebotomy. Patients complete the MPN-SAF for seven consecutive days at enrollment and repeat the survey for an additional seven consecutive days between 90 days and six months. Patients also complete the European Organisation for Research and Treatment of Cancer (EORTC) and M.D. Anderson Symptom Inventory (MDASI) instruments at enrollment and on the first day of the second assessment. At visits, physicians acquired demographic, laboratory, physical examination, and radiographic data. Descriptive statistics were used to summarize data. Results: Clinical Data The MEASURE trial opened for enrollment in 2012 and remains in recruitment phase with 15 participating international sites. To date, 39 patients have been enrolled and 25 have completed both study visits. Participants include ET (28%), PV (24%), and MF (48%; 50% primary MF, 8% post-ET, 42% post-PV) patients. The majority of patients are male (64%) and of expected age (mean 69.3, range 39-89) for the disorders. Seventeen percent had prior thrombosis, 9% required red blood cell transfusion, and none reported prior splenectomy or hemorrhage. Mean hematologic measures included hemoglobin 13.2 g/dL, WBC count 11.4 x109/L, ANC 8.5 x109/L, and platelets 514 x109/L. Therapies received prior to enrollment included aspirin (n=16), hydroxyurea (n=11), phlebotomy (n=8), warfarin/clopidogrel/anticoagulation (n=8), erythropoietin (n=2), and interferon (n=1). The most common current MPN therapies were hydroxyurea (n=9), aspirin (n=9), interferon (n=4), and phlebotomy (n=2). Symptom Assessment In comparing MPN-SAF TSS mean symptom scores, all symptoms except bony pain improved between the first and second visits, including fatigue, early satiety, abdominal discomfort, inactivity, concentration, night sweats, itching, fever, weight loss, and overall quality of life (Figure1). Total MPN-SAF TSS scores improved from a mean of 32.3 to 25.9. On the EORTC, mean scores for physical, role, emotional, and social functioning improved from the first to the second visit (Figure 2). Cognitive functioning showed a slight decline. Global health status measure improved from 60.2 to 72.9. On the MDASI, symptom severity scores decreased from 3.6 to 2.8 from the first to second visit (Figure 3). Symptom distress measure decreased from 4.1 to 3.0. Discussion: Interim results from the MEASURE trial demonstrate that standard, non-experimental treatment regimens offer improvement in quality of life-related symptoms on multiple patient-reported survey instruments including the MPN-SAF TSS, EORTC QLQ-C30, and MDASI. Updated data including symptom correlations and mutational analysis to be presented at the 2016 ASH conference. Disclosures Ross: Novartis Pharmaceuticals: Honoraria, Research Funding; BMS: Honoraria. Radia:Novartis: Honoraria; Pfizer: Honoraria. McMullin:Novartis: Honoraria, Speakers Bureau. Cargo:Novartis: Honoraria; Celgene: Honoraria, Research Funding. Sekhar:Novartis: Research Funding. Mesa:Gilead: Research Funding; CTI Biopharma: Research Funding; Galena: Consultancy; Ariad: Consultancy; Incyte: Research Funding; Novartis: Consultancy; Celgene: Research Funding; Promedior: Research Funding.
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Bolis, G., G. Favalli, S. Danese, F. Zanaboni, G. Mangili, C. Scarabelli, S. Tateo, et al. "Weekly cisplatin given for 2 months versus cisplatin plus cyclophosphamide given for 5 months after cytoreductive surgery for advanced ovarian cancer." Journal of Clinical Oncology 15, no. 5 (May 1997): 1938–44. http://dx.doi.org/10.1200/jco.1997.15.5.1938.
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PURPOSE To compare the efficacy of a treatment with cisplatin plus cyclophosphamide given for 5 months and a short treatment with cisplatin alone in advanced ovarian cancer, we conducted a multicenter randomized clinical trial. PATIENTS AND METHODS Eligibility criteria were as follows: first diagnosis of histologically confirmed invasive epithelial ovarian cancer of International Federation of Gynecology and Obstetric (FIGO) stage III-IV, age younger than 75 years, and Eastern Cooperative Oncology Group (ECOG) performance status 0, 1, or 2. Within 28 days of cytoreductive surgery, eligible women were randomly assigned treatment with weekly cisplatin 50 mg/m2 for nine courses or cisplatin 75 mg/m2 plus cyclophosphamide 750 mg/m2 every 21 days for six courses. RESULTS A total of 607 women were entered onto the study. There was no difference in the response to treatment. Pathologic complete response (CR) was documented in 63 of the weekly cisplatin cases and 70 of the cisplatin plus cyclophosphamide group (chi 1(2) = 1.43; P = .23). The median follow-up time was 3 years. There were 151 and 148 deaths in the weekly cisplatin and cyclophosphamide plus cisplatin arms, respectively. Survival curves were similar in the two groups, with a 3-year percent survival estimate of 44.1 (SE = 3.4) in the weekly cisplatin and 44.6 (SE = 3.4) in the cisplatin plus cyclophosphamide group (log-rank test chi 1(2) = 0.004; P = .96). CONCLUSION This study found that 2-month monochemotherapy treatment with cisplatin was as effective as 5-month polychemotherapy including cisplatin at a similar doses but different dose-intensity plus cyclophosphamide.
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Ryan, Christopher W., Ofer Merimsky, Mark Agulnik, Jean-Yves Blay, Scott M. Schuetze, Brian A. Van Tine, Robin L. Jones, et al. "PICASSO III: A Phase III, Placebo-Controlled Study of Doxorubicin With or Without Palifosfamide in Patients With Metastatic Soft Tissue Sarcoma." Journal of Clinical Oncology 34, no. 32 (November 10, 2016): 3898–905. http://dx.doi.org/10.1200/jco.2016.67.6684.
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Purpose Palifosfamide is the active metabolite of ifosfamide and does not require prodrug activation, thereby avoiding the generation of toxic metabolites. The PICASSO III trial compared doxorubicin plus palifosfamide with doxorubicin plus placebo in patients who had received no prior systemic therapy for metastatic soft tissue sarcoma. Patients and Methods Patients were randomly assigned 1:1 to receive doxorubicin 75 mg/m2 intravenously day 1 plus palifosfamide 150 mg/m2/d intravenously days 1 to 3 or doxorubicin plus placebo once every 21 days for up to six cycles. The primary end point was progression-free survival (PFS) by independent radiologic review. Results In all, 447 patients were randomly assigned to receive doxorubicin plus palifosfamide (n = 226) or doxorubicin plus placebo (n = 221). Median PFS was 6.0 months for doxorubicin plus palifosfamide and 5.2 months for doxorubicin plus placebo (hazard ratio, 0.86; 95% CI, 0.68 to 1.08; P = .19). Median overall survival was 15.9 months for doxorubicin plus palifosfamide and 16.9 months for doxorubicin plus placebo (hazard ratio, 1.05; 95% CI, 0.79 to 1.39; P = .74). There was a higher incidence of grade 3 to 4 adverse events in the doxorubicin plus palifosfamide arm (63.6% v 50.9%) including a higher rate of febrile neutropenia (21.4% v 12.6%). Conclusion No significant difference in PFS was observed in patients receiving doxorubicin plus palifosfamide compared with those receiving doxorubicin plus placebo. The observed median PFS and overall survival in this large, international study can serve as a benchmark for future studies of doxorubicin in metastatic soft tissue sarcoma.
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Martínez-Fernández, María Isabel, Jairo Legaspi Folgueira, Germán Valtueña Peydró, Mauricio Cambeiro, Jaime Espinós, José Manuel Aramendía, José A. Minguez-Milio, and Rafael Martínez-Monge. "Long-Term Results of a Phase II Trial of Concomitant Cisplatin-Paclitaxel Chemoradiation in Locally Advanced Cervical Cancer." International Journal of Gynecologic Cancer 26, no. 6 (July 2016): 1162–68. http://dx.doi.org/10.1097/igc.0000000000000744.
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ObjectivesThe aim of this study was to determine the long-term results of a 7-week schedule of external beam radiation therapy, high dose rate brachytherapy, and weekly cisplatin and paclitaxel in patients with locally advanced carcinoma of the cervix.MethodsThirty-seven patients with International Federation of Gynecology and Obstetrics stages IB2 to IVa cervical cancer were treated with 40 mg/m2 per week of intravenous cisplatin and 50 mg/m2 per week of intravenous paclitaxel combined with 45 Gy of pelvic external beam radiation therapy and 28 to 30 Gy of high dose rate brachytherapy.ResultsSixteen patients (43.2%) were able to complete the 6 scheduled cycles of chemotherapy. The median number of weekly chemotherapy cycles administered was 5. Thirty-six (16.2%) of 222 cycles of chemotherapy were not given because of toxicity. The mean dose intensity of cisplatin was 29.6 mg/m2 per week (95% confidence interval, 27.0–32.1); that of paclitaxel was 40.0 mg/m2 per week (95% confidence interval, 36.9–43.1). Thirty-four patients (91.8%) completed the planned radiation course in less than 7 weeks. Median radiation treatment length was 43 days. After a median follow-up of 6 years, 7 patients (18.9%) experienced severe (RTOG grade 3 or higher) late toxicity. No fatal events were observed. Ten patients have failed, 1 locally and 9 at distant sites. The 14-year locoregional control rate was 96.7%, and the 14-year freedom from systemic failure rate was 64.6%. Fourteen-year actuarial disease-free survival and overall survival rates were 44.8% and 50%, respectively.ConclusionsThis study demonstrates excellent very long-term results and tolerable toxicity although the target weekly dosage of cisplatin and paclitaxel needs to be adjusted in the majority of the patients.
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Nasiro, Kalifa. "INFLUENCE OF SEED INITIAL MOISTURE CONTENT, STORAGE CONDITION AND TIME OF STORAGE ON SEEDLING GROWTH STAGES OF COFFEE (COFFEA ARABICA L.)." Agrobiological Records 4 (2021): 1–7. http://dx.doi.org/10.47278/journal.abr/2020.024.
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Coffee is one of the most important agricultural products in the international market and many countries are involved in its production, trade or consumption. Arabica coffee is self-pollinated, homozygous, and normally propagated by seeds. Seeds have been considered intermediate storage behavior with varying results. It is highly desirable that seeds are stored safely to optimize coffee seedling production at the appropriate time and season. The objective of this study was to evaluate the effect of storage temperature, time of storage and initial seed moisture contents on early seedling performances of coffee seeds and to determine the appropriate seed handling method. In this experiment, the influence of initial seed moisture content with four levels (12, 17, 22 & 27%) with storage two temperature (15oC & ambient), time of storage with six levels (sowing after each month and upto 6 months) and on coffee seedling growth stages were studied in a split-split-plot factorial design. The data collected were subjected to ANOVA. The storage environment with cold temperature (15oC) accelerated seedling growth stages parameters much better performances than did ambient temperature condition. All tested seedling growth stages were faster at initial time of storage. After third month seed quality drastically reduced especially under ambient storage condition. Seeds dried to 12% moisture content showed delayed performance throughout the trial period. Seeds with 27% initial moisture content took shorter days to reach at different growth stages at initial storage time but when aged took much days. Storage temperature, time of storage and initial seed moisture contents showed highly significant main and interaction effects and seeds dried to intermediate moisture level (17 and 22%), stored under cold temperature and sown at early times resulted in enhanced seedling growth. It was concluded that drying coffee seeds to 17% to 22% moisture contents and kept under storage with relatively lower temperatures (15oC) for not more than six months of storage showed better performance.
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Basser, Russell L., L. Bik To, John P. Collins, C. Glenn Begley, Dorothy Keefe, Jonathan Cebon, John Bashford, et al. "Multicycle High-Dose Chemotherapy and Filgrastim-Mobilized Peripheral-Blood Progenitor Cells in Women With High-Risk Stage II or III Breast Cancer: Five-Year Follow-Up." Journal of Clinical Oncology 17, no. 1 (January 1999): 82. http://dx.doi.org/10.1200/jco.1999.17.1.82.
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PURPOSE: To determine the safety and efficacy of multiple cycles of dose-intensive, nonablative chemotherapy in women with poor-prognosis breast cancer. PATIENTS AND METHODS: Women with stage II breast cancer and 10 or more involved nodes or four or more involved nodes and estrogen receptor–negative tumors and women with stage III disease received three cycles of epirubicin 200 mg/m2 and cyclophosphamide 4 g/m2, with progenitor cell and filgrastim support every 28 days (n = 79) or 21 days (n = 20). Patients were reviewed at least twice yearly thereafter. Twenty-six patients had bone marrow and apheresis collections assessed for the presence of micrometastatic tumor cells. RESULTS: Ninety-nine women (median age, 43 years; range, 24 to 60 years) were treated. Ninety-two completed all three cycles of chemotherapy. The major toxicity was severe, reversible myelosuppression that was more prolonged with successive cycles, and this did not differ between patients given treatment every 28 days and those treated every 21 days. Febrile neutropenia occurred in 176 (61%) of 287 cycles. Severe mucositis (grade 3 or 4) occurred in 23% of cycles but tended to be short-lived and was reversible. The cardiac ejection fraction fell by a median of 4% during treatment, and three patients developed evidence of cardiac failure after chemotherapy. Two patients (2%) died of acute toxicity. Three of 26 patients had evidence of circulating micrometastatic tumor cells. The actuarial distant disease-free and overall survival rates at 60-month follow-up were 64% (95% confidence interval [CI], 53% to 75%) and 67% (95% CI, 56% to 78%), respectively. CONCLUSION: Multiple cycles of dose-intensive, nonablative chemotherapy is a feasible and safe approach. Disease control and survival are similar to those in other studies of myeloablative chemotherapy in poor-prognosis breast cancer. The regimen is being evaluated in a randomized trial of the International Breast Cancer Study Group.
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Tsimberidou, Apostolia, Kerstin Guenther, Amir Alpert, Borje Andersson, Zoe Coughlin, Jens Fritsche, Norbert Hilf, et al. "293 Resultsof the first-in-human clinical trial with personalized multi-target adoptive cell therapy (ACTolog IMA101)." Journal for ImmunoTherapy of Cancer 8, Suppl 3 (November 2020): A320. http://dx.doi.org/10.1136/jitc-2020-sitc2020.0293.
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BackgroundACTolog (IMA101) is a personalized multi-target adoptive cell therapy (ACT) approach in which autologous T-cell products are redirected against multiple novel defined peptide-HLA (pHLA) cancer targets identified by the target discovery platform XPRESIDENT®. The primary endpoint was to assess the safety of ACTolog. Secondary endpoints were to assess the in vivo persistence of transferred T-cells and antitumor activity (www.clinicaltrials.gov NCT02876510).MethodsHLA-A*02:01 positive patients with relapsed/refractory solid tumors whose tumor expressed ≥1 cancer target underwent leukapheresis and endogenous T-cells specific for up to 4 targets were primed and expanded in vitro. Patients received lymphodepletion (fludarabine 40 mg/m² and cyclophosphamide 500 mg/m² on days -6 to -3) followed by up to 4 × 1010 cells (day 0), and IL-2 (1 × 106 IU/m² SC twice daily, 14 days) (Cohort 1). In addition, cohort 2 received atezolizumab (1200 mg IV) every 21 days upon hematologic recovery. Infused T-cells were tracked in patients‘ blood via flow cytometry-based immunomonitoring as well as TCRβ sequencing. TCRs from target specific T-cells were identified from patients‘ T-cell products and characterized.ResultsFrom 07/2017–03/2020, 214 patients were screened, and 14 heavily pre-treated patients with various tumor types were infused with 1–3 T-cell products each (table 1). The treatment was generally well tolerated. The most common adverse events observed to date were expected cytopenias, mostly attributed to the lymphodepleting regimen, and Grade 1–2 cytokine release syndrome. Prolonged disease stabilization was noted in three patients for 12 months, 12+ months, and 7 months. High frequencies of target-specific T-cells up to 78.7% of CD8+ cells were detected in the blood of treated patients, persisted for >1 year and were detected in post-treatment tumor biopsies. Characterization of individual TCRs contained in T-cell products showed a broad variation of TCR avidities with the majority of TCRs being of low avidity. High-avidity TCRs were identified from products of some patients, including a patient with 26% decrease in tumor measurements 6 weeks post-treatment. Tracking the respective T-cell clonotypes in patients‘ blood and tumor provides insights into the mechanism of tumor control. Six-month data will be presented at the conference.Abstract 293 Table 1Patient pre-treatment characteristics and response assessmentConclusionsThis is the first reported trial demonstrating the feasibility and tolerability of a personalized ACT approach using multiple defined T-cell products directed to multiple precisely defined pHLA cancer targets. These results support further exploration of a multi-target ACT approach, particularly in the context of T-cells expressing high-avidity TCRs to such defined pHLA targets.Trial Registrationhttps://clinicaltrials.gov/ct2/show/NCT02876510Ethics ApprovalThe study was approved by WCG WIRB, IRB tracking number 20162235. The study was conducted in accordance with the Declaration of Helsinki and the International Conference on Harmonization Good Clinical Practice guidelines. All the study participants provided written informed consent before enrollment.ConsentPatient consent for publication is not required. Patients consented to participate in the study.