Osteosarcoma is the most common primary bone sarcoma and is often diagnosed in the 2nd-3rd decades of life. Response to the aggressive and highly toxic neoadjuvant methotrexate-doxorubicin-cisplatin ...(MAP) chemotherapy schedule is strongly predictive of outcome. Outcomes for patients with osteosarcoma have not significantly changed for over thirty years. There is a need for more effective treatment for patients with high risk features but also reduced treatment-related toxicity for all patients. Predictive biomarkers are needed to help inform clinicians to de-escalate or add therapy, including immune therapies, and to contribute to future clinical trial designs. Here, we review a variety of approaches to improve outcomes and quality of life for patients with osteosarcoma with a focus on incorporating toxicity reduction, immune therapy and molecular analysis to provide the most effective and least toxic osteosarcoma therapy.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Opioid use for pain management has dramatically increased, with little assessment of potential pathophysiological consequences for the primary pain condition. Here, a short course of morphine, ...starting 10 d after injury in male rats, paradoxically and remarkably doubled the duration of chronic constriction injury (CCI)-allodynia, months after morphine ceased. No such effect of opioids on neuropathic pain has previously been reported. Using pharmacologic and genetic approaches, we discovered that the initiation and maintenance of this multimonth prolongation of neuropathic pain was mediated by a previously unidentified mechanism for spinal cord and pain—namely, morphine-induced spinal NOD-like receptor protein 3 (NLRP3) inflammasomes and associated release of interleukin-1β (IL-1β). As spinal dorsal horn microglia expressed this signaling platform, these cells were selectively inhibited in vivo after transfection with a novel Designer Receptor Exclusively Activated by Designer Drugs (DREADD). Multiday treatment with the DREADD-specific ligand clozapine-N-oxide prevented and enduringly reversed morphine-induced persistent sensitization for weeks to months after cessation of clozapine-N-oxide. These data demonstrate both the critical importance of microglia and that maintenance of chronic pain created by early exposure to opioids can be disrupted, resetting pain to normal. These data also provide strong support for the recent “two-hit hypothesis” of microglial priming, leading to exaggerated reactivity after the second challenge, documented here in the context of nerve injury followed by morphine. This study predicts that prolonged pain is an unrealized and clinically concerning consequence of the abundant use of opioids in chronic pain.
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BFBNIB, NMLJ, NUK, PNG, SAZU, UL, UM, UPUK
Montminy EM, Zhou M, Maniscalco L, et al.
Contributions of adenocarcinoma and carcinoid tumors to early-onset colorectal cancer incidence rates in the United States. Ann Intern Med 2021;174:157–166.
B-cell maturation antigen (BCMA) is a cell-surface receptor of the tumour necrosis superfamily required for plasma cell survival. BMCA is universally detected on patient-derived myeloma cells and has ...emerged as a selective antigen to be targeted by novel treatments in multiple myeloma. We assessed the safety, tolerability, and preliminary clinical activity of GSK2857916, a novel anti-BCMA antibody conjugated to microtubule-disrupting agent monomethyl auristatin F, in patients with relapsed and refractory multiple myeloma.
We did an international, multicentre, open-label, first-in-human phase 1 study with dose escalation (part 1) and dose expansion (part 2) phases, at nine centres in the USA, Canada, and the UK. Adults with histologically or cytologically confirmed multiple myeloma, Eastern Cooperative Oncology Group performance status 0 or 1, and progressive disease after stem cell transplantation, alkylators, proteasome inhibitors, and immunomodulators were recruited for this study. In part 1, patients received GSK2857916 (0·03–4·60 mg/kg) through 1 h intravenous infusions once every 3 weeks. In part 2, patients received the selected recommended phase 2 dose of GSK2857916 (3·40 mg/kg) once every 3 weeks. Primary endpoints were maximum tolerated dose and recommended phase 2 dose. Secondary endpoints for part 2 included preliminary anti-cancer clinical activity. All patients who received one or more doses were included in this prespecified administrative interim analysis (data cutoff date June 26, 2017), which was done for internal purposes. This study is registered with ClinicalTrials.gov, number NCT02064387, and is ongoing, but closed for recruitment.
Between July 29, 2014, and Feb 21, 2017, we treated 73 patients: 38 patients in the dose-escalation part 1 and 35 patients in the dose-expansion part 2. There were no dose-limiting toxicities and no maximum tolerated dose was identified in part 1. On the basis of safety and clinical activity, we selected 3·40 mg/kg as the recommended phase 2 dose. Corneal events were common (20 53% of 38 patients in part 1 and 22 63% of 35 in part 2); most (18 47% in part 1 and 19 54% in part 2) were grade 1 or 2 and resulted in two treatment discontinuations in part 1 and no discontinuations in part 2. The most common grade 3 or 4 events were thrombocytopenia (13 34% of 38 patients in part 1 and 12 34% of 35 in part 2) and anaemia (6 16% in part 1 and 5 14% in part 2). There were 12 treatment-related serious adverse events and no treatment-related deaths. In part 2, 21 (60·0%; 95% CI 42·1–76·1) of 35 patients achieved an overall response.
At the identified recommended phase 2 dose, GSK2857916 was well tolerated and had good clinical activity in heavily pretreated patients, thereby indicating that this might be a promising candidate for the treatment of relapsed or refractory multiple myeloma.
GlaxoSmithKline.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK, ZRSKP
The lack of consistent, accurate information on evapotranspiration (ET) and consumptive use of water by irrigated agriculture is one of the most important data gaps for water managers in the western ...United States (U.S.) and other arid agricultural regions globally. The ability to easily access information on ET is central to improving water budgets across the West, advancing the use of data‐driven irrigation management strategies, and expanding incentive‐driven conservation programs. Recent advances in remote sensing of ET have led to the development of multiple approaches for field‐scale ET mapping that have been used for local and regional water resource management applications by U.S. state and federal agencies. The OpenET project is a community‐driven effort that is building upon these advances to develop an operational system for generating and distributing ET data at a field scale using an ensemble of six well‐established satellite‐based approaches for mapping ET. Key objectives of OpenET include: Increasing access to remotely sensed ET data through a web‐based data explorer and data services; supporting the use of ET data for a range of water resource management applications; and development of use cases and training resources for agricultural producers and water resource managers. Here we describe the OpenET framework, including the models used in the ensemble, the satellite, meteorological, and ancillary data inputs to the system, and the OpenET data visualization and access tools. We also summarize an extensive intercomparison and accuracy assessment conducted using ground measurements of ET from 139 flux tower sites instrumented with open path eddy covariance systems. Results calculated for 24 cropland sites from Phase I of the intercomparison and accuracy assessment demonstrate strong agreement between the satellite‐driven ET models and the flux tower ET data. For the six models that have been evaluated to date (ALEXI/DisALEXI, eeMETRIC, geeSEBAL, PT‐JPL, SIMS, and SSEBop) and the ensemble mean, the weighted average mean absolute error (MAE) values across all sites range from 13.6 to 21.6 mm/month at a monthly timestep, and 0.74 to 1.07 mm/day at a daily timestep. At seasonal time scales, for all but one of the models the weighted mean total ET is within ±8% of both the ensemble mean and the weighted mean total ET calculated from the flux tower data. Overall, the ensemble mean performs as well as any individual model across nearly all accuracy statistics for croplands, though some individual models may perform better for specific sites and regions. We conclude with three brief use cases to illustrate current applications and benefits of increased access to ET data, and discuss key lessons learned from the development of OpenET.
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FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
Summary Background High blood pressure is a prognostic factor for acute stroke, but blood pressure variability might also independently predict outcome. We assessed the prognostic value of blood ...pressure variability in participants of INTERACT2, an open-label randomised controlled trial ( ClinicalTrials.gov number NCT00716079 ). Methods INTERACT2 enrolled 2839 adults with spontaneous intracerebral haemorrhage (ICH) and high systolic blood pressure (150–220 mm Hg) without a definite indication or contraindication to early intensive treatment to reduce blood pressure. Participants were randomly assigned to intensive treatment (target systolic blood pressure <140 mm Hg within 1 h using locally available intravenous drugs) or guideline-recommended treatment (target systolic blood pressure <180 mm Hg) within 6 h of onset of ICH. The primary outcome was death or major disability at 90 days (modified Rankin Scale score ≥3) and the secondary outcome was an ordinal shift in modified Rankin Scale scores at 90 days, assessed by investigators masked to treatment allocation. Blood pressure variability was defined according to standard criteria: five measurements were taken in the first 24 h (hyperacute phase) and 12 over days 2–7 (acute phase). We estimated associations between blood pressure variability and outcomes with logistic and proportional odds regression models. The key parameter for blood pressure variability was standard deviation (SD) of systolic blood pressure, categorised into quintiles. Findings We studied 2645 (93·2%) participants in the hyperacute phase and 2347 (82·7%) in the acute phase. In both treatment cohorts combined, SD of systolic blood pressure had a significant linear association with the primary outcome for both the hyperacute phase (highest quintile adjusted OR 1·41, 95% CI 1·05–1·90; ptrend =0·0167) and the acute phase (highest quintile adjusted OR 1·57, 95% CI 1·14–2·17; ptrend =0·0124). The strongest predictors of outcome were maximum systolic blood pressure in the hyperacute phase and SD of systolic blood pressure in the acute phase. Associations were similar for the secondary outcome (for the hyperacute phase, highest quintile adjusted OR 1·43, 95% CI 1·14–1·80; ptrend =0·0014; for the acute phase OR 1·46, 95% CI 1·13–1·88; ptrend =0·0044). Interpretation Systolic blood pressure variability seems to predict a poor outcome in patients with acute intracerebral haemorrhage. The benefits of early treatment to reduce systolic blood pressure to 140 mm Hg might be enhanced by smooth and sustained control, and particularly by avoiding peaks in systolic blood pressure. Funding National Health and Medical Research Council of Australia.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
IMPORTANCE: Pulmonary vein isolation (PVI) alone is less effective in patients with persistent atrial fibrillation (AF) compared with paroxysmal AF. The left atrial posterior wall may contribute to ...maintenance of persistent AF, and posterior wall isolation (PWI) is a common PVI adjunct. However, PWI has not been subjected to randomized comparison. OBJECTIVE: To compare PVI with PWI vs PVI alone in patients with persistent AF undergoing first-time catheter ablation. DESIGN, SETTING, AND PARTICIPANTS: Investigator initiated, multicenter, randomized clinical trial involving 11 centers in 3 countries (Australia, Canada, UK). Symptomatic patients with persistent AF were randomized 1:1 to either PVI with PWI or PVI alone. Patients were enrolled July 2018-March 2021, with 1-year follow-up completed March 2022. INTERVENTIONS: The PVI with PWI group (n = 170) underwent wide antral pulmonary vein isolation followed by posterior wall isolation involving linear ablation at the roof and floor to achieve electrical isolation. The PVI-alone group (n = 168) underwent wide antral pulmonary vein isolation alone. MAIN OUTCOMES AND MEASURES: Primary end point was freedom from any documented atrial arrhythmia of more than 30 seconds without antiarrhythmic medication at 12 months, after a single ablation procedure. The 23 secondary outcomes included freedom from atrial arrhythmia with/without antiarrhythmic medication after multiple procedures, freedom from symptomatic AF with/without antiarrhythmic medication after multiple procedures, AF burden between study groups at 12 months, procedural outcomes, and complications. RESULTS: Among 338 patients randomized (median age, 65.6 IQR, 13.1 years; 76.9% men), 330 (97.6%) completed the study. After 12 months, 89 patients (52.4%) assigned to PVI with PWI were free from recurrent atrial arrhythmia without antiarrhythmic medication after a single procedure, compared with 90 (53.6%) assigned to PVI alone (between-group difference, –1.2%; hazard ratio HR, 0.99 95% CI, 0.73-1.36; P = .98). Of the secondary end points, 9 showed no significant difference, including freedom from atrial arrhythmia with/without antiarrhythmic medication after multiple procedures (58.2% for PVI with PWI vs 60.1% for PVI alone; HR, 1.10 95% CI, 0.79-1.55; P = .57), freedom from symptomatic AF with/without antiarrhythmic medication after multiple procedures (68.2% vs 72%; HR, 1.20 95% CI, 0.80-1.78; P = .36) or AF burden (0% IQR, 0%-2.3% vs 0% IQR, 0%-2.8%, P = .47). Mean procedural times (142 SD, 69 vs 121 SD, 57 minutes, P < .001) and ablation times (34 SD, 21 vs 28 SD, 12 minutes, P < .001) were significantly shorter for PVI alone. There were 6 complications for PVI with PWI and 4 for PVI alone. CONCLUSIONS AND RELEVANCE: In patients undergoing first-time catheter ablation for persistent AF, the addition of PWI to PVI alone did not significantly improve freedom from atrial arrhythmia at 12 months compared with PVI alone. These findings do not support the empirical inclusion of PWI for ablation of persistent AF. TRIAL REGISTRATION: anzctr.org.au Identifier: ACTRN12616001436460
WHAT WE ALREADY KNOW ABOUT THIS TOPICElectromagnetic interference from monopolar electrosurgery may disrupt implantable cardioverter defibrillators.Current management recommendations by the American ...Society of Anesthesiologists and Heart Rhythm Society are based on expert clinical opinion since there is a paucity of data regarding the risk of electromagnetic interference to implantable cardioverter defibrillators during surgery.
WHAT THIS ARTICLE TELLS US THAT IS NEWWith protocolized electrosurgery dispersive electrode positioning in patients with implantable cardioverter defibrillators, the risk of clinically meaningful electromagnetic interference was 7% in above-the-umbilicus noncardiac surgery and 0% in below-the-umbilicus surgery. In cardiac surgery, clinically meaningful electromagnetic interference with use of an underbody dispersive electrode was 29%.Despite protocolized dispersive electrode positioning, the risk of electromagnetic interference in above-the-umbilicus surgery is high, supporting recommendations to suspend antitachycardia therapy when monopolar electrosurgery is used above the umbilicus.With protocolized dispersive electrode positioning, the risk of electromagnetic interference in below-the-umbilicus surgery is negligible, implying that suspending antitachycardia therapy might be unnecessary in these cases.With an underbody dispersive electrode, the risk of electromagnetic interference in cardiac surgery is high.
BACKGROUND:The goal of this study was to determine the occurrence of intraoperative electromagnetic interference from monopolar electrosurgery in patients with an implantable cardioverter defibrillator undergoing surgery. A protocolized approach was used to position the dispersive electrode.
METHODS:This was a prospective cohort study including 144 patients with implantable cardioverter defibrillators undergoing surgery between May 2012 and September 2016 at an academic medical center. The primary objectives were to determine the occurrences of electromagnetic interference and clinically meaningful electromagnetic interference (interference that would have resulted in delivery of inappropriate antitachycardia therapy had the antitachycardia therapy not been programmed off) in noncardiac surgeries above the umbilicus, noncardiac surgeries at or below the umbilicus, and cardiac surgeries with the use of an underbody dispersive electrode.
RESULTS:The risks of electromagnetic interference and clinically meaningful electromagnetic interference were 14 of 70 (20%) and 5 of 70 (7%) in above-the-umbilicus surgery, 1 of 40 (2.5%) and 0 of 40 (0%) in below-the-umbilicus surgery, and 23 of 34 (68%) and 10 of 34 (29%) in cardiac surgery. Had conservative programming strategies intended to reduce the risk of inappropriate antitachycardia therapy been employed, the occurrence of clinically meaningful electromagnetic interference would have been 2 of 70 (2.9%) in above-the-umbilicus surgery and 3 of 34 (8.8%) in cardiac surgery.
CONCLUSIONS:Despite protocolized dispersive electrode positioning, the risks of electromagnetic interference and clinically meaningful electromagnetic interference with surgery above the umbilicus were high, supporting published recommendations to suspend antitachycardia therapy whenever monopolar electrosurgery is used above the umbilicus. For surgery below the umbilicus, these risks were negligible, implying that suspending antitachycardia therapy is likely unnecessary in these patients. For cardiac surgery, the risks of electromagnetic interference and clinically meaningful electromagnetic interference with an underbody dispersive electrode were high. Conservative programming strategies would not have eliminated the risk of clinically meaningful electromagnetic interference in either noncardiac surgery above the umbilicus or cardiac surgery.
Objectives This study sought to compare all-cause mortality in patients at intermediate surgical risk undergoing transcatheter aortic valve implantation (TAVI) or surgical aortic valve replacement ...(SAVR). Background Physicians are selecting “lower” surgical risk patients to undergo TAVI. No clinical data exist about the clinical outcomes of TAVI versus SAVR among intermediate-surgical-risk patients. Methods We prospectively enrolled symptomatic patients with severe aortic stenosis who underwent TAVI or SAVR. Propensity-score matched pairs of TAVI and SAVR patients with Society of Thoracic Surgeons (STS) scores between 3% and 8% made up the study population. Primary endpoint was all-cause mortality at 1 year. Results Between November 2006 and January 2010, 3,666 consecutive patients underwent either TAVI (n = 782) or SAVR (n = 2,884). Four hundred five TAVI patients were matched to 405 SAVR patients. Of matched TAVI patients, 99 (24%) patients had STS scores <3%, 255 (63%) had scores between 3% and 8%, and 51 (13%) had scores >8%. Among patients with STS scores between 3% and 8%, 20 (7.8%) versus 18 (7.1%) patients had died up to 30 days (hazard ratio: 1.12, 95% confidence interval: 0.58 to 2.15, p = 0.74) and 42 (16.5%) versus 43 (16.9%) patients had died up to 1 year (hazard ratio: 0.90, 95% confidence interval: 0.57 to 1.42, p = 0.64) after TAVI and SAVR, respectively. Effects of treatment on 1-year mortality were similar across all subgroups except for sex, with some evidence for a beneficial effect of TAVI in women but not in men (test for interaction p = 0.024). Conclusions Cumulative all-cause mortality at 30 days and 1 year was similar among propensity-score matched TAVI and SAVR patients at intermediate surgical risk. (Surgical Replacement and Transcatheter Aortic Valve Implantation SURTAVI; NCT01586910 )
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Exercise is known to exert a systemic anti-inflammatory influence, but whether its effects are sufficient to protect against subsequent neuropathic pain is underinvestigated. We report that 6 weeks ...of voluntary wheel running terminating before chronic constriction injury (CCI) prevented the full development of allodynia for the ∼3-month duration of the injury. Neuroimmune signaling was assessed at 3 and 14 days after CCI. Prior exercise normalized ipsilateral dorsal spinal cord expression of neuroexcitatory interleukin (IL)-1β production and the attendant glutamate transporter GLT-1 decrease, as well as expression of the disinhibitory P2X4R-BDNF axis. The expression of the macrophage marker Iba1 and the chemokine CCL2 (MCP-1), and a neuronal injury marker (activating transcription factor 3), was attenuated by prior running in the ipsilateral lumbar dorsal root ganglia. Prior exercise suppressed macrophage infiltration and/or injury site proliferation, given decreased presence of macrophage markers Iba1, iNOS (M1), and Arg-1 (M2; expression was time dependent). Chronic constriction injury-driven increases in serum proinflammatory chemokines were suppressed by prior running, whereas IL-10 was increased. Peripheral blood mononuclear cells were also stimulated with lipopolysaccharide ex vivo, wherein CCI-induced increases in IL-1β, nitrite, and IL-10 were suppressed by prior exercise. Last, unrestricted voluntary wheel running, beginning either the day of, or 2 weeks after, CCI, progressively reversed neuropathic pain. This study is the first to investigate the behavioral and neuroimmune consequences of regular exercise terminating before nerve injury. This study suggests that chronic pain should be considered a component of "the diseasome of physical inactivity," and that an active lifestyle may prevent neuropathic pain.
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