Explosives are often used in industry, geology, mining, and other applications, but it is not always clear what remains after a detonation or the fate and transport of any residual material. The goal ...of this study was to determine to what extent intact molecules of high explosive (HE) compounds are detectable and quantifiable from post-detonation dust and particulates in a field experiment with varied topography. We focused on HMX (1,3,5,7-Tetranitro-1,3,5,7-tetrazocane), which is less studied in field detonation literature, as the primary explosive material and RDX (1,3,5-Trinitroperhydro-1,3,5-triazine) as the secondary material. The experiment was conducted at Site 300, Lawrence Livermore National Laboratory's Experimental Test Site, in California, USA. Two 20.4 kg and one 40.8 kg above ground explosions (primarily comprised of LX-14, an HMX-based polymer-bonded high explosive) were detonated on an open-air firing area on separate days. The complex terrain of the firing area (e.g., buildings, berm, low-height obstacles) was advantageous to study HE deposition in relation to plume dynamics.
Three types of samples were collected up to 100 m away from each shot: surface swipes of aluminum plates, surface swipes of fixed objects, and filters from air samples. We used atmospheric flow tube-mass spectrometry (AFT-MS) to quantify picogram levels of molecular residue of HE material in the post-detonation dust. An aliquot of sample extract in methanol (e.g., 1 μL of 0.5 mL) was placed onto a resistive material and then thermally desorbed into the AFT-MS. We successfully detected and quantified both HMX and RDX in many of the samples. Based on mass (pg) detected and solution dilution, we back-calculated the mass collected on the swipe or filter (ng per sample). The aerial distribution of molecular residue was consistent with the path of the plume, which was strongly determined by wind speed and direction at the time of each shot. The quantity of material detected appeared to correlate more with distance from the shot and the wind conditions than with shot size. This study demonstrates that the picogram detection levels of AFT-MS are well-suited for quantification of analytes (e.g., HMX and RDX) in environmental samples.
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•Trace explosive residue detection in post-detonation dust from open-air environment.•Explosive residue sampled from small surface areas up to 100 m from detonation.•Used atmospheric flow tube-mass spectrometry to detect picograms of HMX and RDX.•Spatial dispersal of molecular HMX and RDX residue followed plume path and wind.•Estimated <1 part per million of explosive remained of original detonated material.
Article Note: .sup.DaggerCollaborators: Shirley D'Sa (Mount Vernon Cancer Centre, Herts), Andres Virchis (Royal Free Hospital Foundation NHS Trust, London), Michael Quinn (Belfast Trust), Charles ...Crawley (Addenbrookes Hospital, Cambridge), Guy Pratt (University Hospitals Birmingham NHS Foundation Trust, Birmingham), Mark Cook (University Hospitals Birmingham NHS Foundation Trust, Birmingham). CAPTION(S): Table SI. Participating centres and recruitment. Table SII. Patient baseline characteristics. Table SIII. Response to PAD induction, and MRD status post-PBSCH and at Day 100. Table SIV. Adverse events in >10% of patients (safety population n = 153). Table SV. Adverse events with a maximum grade ayen3 by term (safety population n = 153). Table SVI. Reasons for those that did not achieve ayenVGPR not proceeding directly to stem cell harvest. Table SVII. Reasons for PR-ASCT patients not proceeding directly to ASCT. Table SVIII. MRD status according to treatment. Table SIX. MRD status according to treatment and cytogenetic risk. Fig S1. CONSORT diagram. Fig S2. Kaplan-Meier plots of progression-free survival-2 by: (A) post-PBSCH response; (B) post-PBSCH response and MRD status at Day 100; (C) MRD status at Day 100. Fig S3. Kaplan-Meier plots for the VGPR-W&W group by cytogenetic risk group: (A) progression-free survival; (B) progression-free survival-2; (C) overall survival. Fig S4. Kaplan-Meier plots for the VGPR-W&W group by cytogenetic risk group and MRD status at Day 100: (A) progression-free survival; (B) progression-free survival-2; (C) overall survival. Fig S5. Kaplan-Meier plots by MRD status at PBSCH of: (A) progression-free survival; (B) progression-free survival-2; (C) overall survival. Byline: Rakesh Popat, Nicholas Counsell, Ruth de Tute, Dunnya De-Silva, Elizabeth H. Phillips, Jamie D. Cavenagh, Toyin Adedayo, Nivette Braganca, Claire Roddie, Matthew Streetly, Steve Schey, Mickey B. C. Koh, Josephine Crowe, Treen C. Morris, Gordon Cook, Paul Smith, Laura Clifton-Hadley, Neil Rabin, Roger Owen, Kwee Yong,
Many type 2 diabetes patients require mealtime insulin to help maintain glycemic control, but this carries a risk of hypoglycemia. Since the glucose-lowering mechanism of SGLT2 inhibitors does not ...require beta-cell function, we asked if addition of the SGLT2 inhibitor canagliflozin (CANA) could “rescue” patients from the need for mealtime insulin. In a pilot study, after 2 week run-in, 26 pts requiring QID basal-bolus insulin with negative GAD antibodies were randomized, double-blind, to CANA or placebo (PLBO); dosage was 100 mg/d for 2 week, then 300 mg/d for 22 week. At baseline, the groups were similar: mean age 64 year, BMI 31.2, 100% male, 64% black, HbA1c 8.0%, insulin 107 units/day, CGM time in range (TIR, 70-180 mg/dl) 75.5%, hypoglycemia (<54 mg/dl) 0.41%, and hyperglycemia (>180 mg/dl) 22.8% (all p>0.05). Over 24 weeks, insulin was adjusted weekly in all pts to improve control but avoid hypoglycemia. One PLBO pt had a penile infection and d/c’d study drug, but other adverse events were similar, and there was no severe hypoglycemia. Among 13 CANA and 11 PLBO pts who followed the protocol for 24 week, during the last 12 week, despite a 27% reduction in insulin dosage to 78 units/day with CANA vs. a 7% increase to 112 units/day with PLBO (p=ns), 37% of CANA pts were able to d/c mealtime Rx entirely, and 4% to switch to glipizide, for >1 meal/day, vs. 32% and 8% with PLBO, respectively (p=ns); CGM metrics were better with CANA as well, TIR 79% vs. 74%, hypoglycemia 0.58% vs. 0.84%, and hyperglycemia 18.7% vs. 23.9% with CANA vs. PLBO, respectively, all p=ns, and HbA1c was 7.4% with CANA vs. 7.6% with PLBO (p=ns).
Conclusions: Addition of canagliflozin to the regimens of patients using basal-bolus insulin, allows some patients to discontinue mealtime medication entirely, and others to switch from insulin to an oral agent, for at least one meal/day, with concomitant improvement in glycemic control, although differences from placebo were not statistically significant in this pilot study. Intensive management allows many patients to reduce their need for mealtime insulin.
Disclosure
L.S. Phillips: Advisory Panel; Self; Janssen Pharmaceuticals, Inc. Research Support; Self; AbbVie Inc., GlaxoSmithKline plc., Kowa Pharmaceutical Europe Co. Ltd., Novartis Pharmaceuticals Corporation, Novo Nordisk Inc., Pfizer Inc. Stock/Shareholder; Self; Diasyst Inc. Other Relationship; Self; Diasyst Inc., Janssen Pharmaceuticals, Inc. F. Morehead: None. L.P. Savoye: None. M.K. Rhee: None. D. Olson: None. E.H. Burgess: None. X. Cui: None. P. Calhoun: Stock/Shareholder; Self; Dexcom, Inc. R. Bailey: None.
Funding
U.S. Department of Veterans Affairs; National Institutes of Health
Summary
Relapsed or refractory classical Hodgkin lymphoma (cHL) is associated with a poor outcome when standard chemotherapy fails. Brentuximab vedotin (BV) is an anti‐CD30 monoclonal antibody‐drug ...conjugate licensed for use at relapse after autologous stem cell transplant (ASCT) or following two prior therapies in those unsuitable for ASCT. There are limited data assessing the ability of BV to enable curative SCT. We performed a UK‐wide retrospective study of 99 SCT‐naïve relapsed/refractory cHL. All had received 2 prior lines and were deemed fit for transplant but had an insufficient remission to proceed. The median age was 32 years. Most had nodular sclerosis subtype, Eastern Cooperative Oncology Group performance status 0–1 and advanced stage disease. The median progression‐free survival (PFS) was 5·6 months and median overall survival (OS) was 37·2 months. The overall response rate was 56% (29% complete response; 27% partial response). 61% reached SCT: 34% immediately post‐BV and 27% following an inadequate BV response but were salvaged and underwent deferred SCT. Patients consolidated with SCT had a superior PFS and OS to those not receiving SCT (P < 0·001). BV is an effective, non‐toxic bridge to immediate SCT in 34% and deferred SCT in 27%. 39% never reached SCT with a PFS of 3·0 months, demonstrating the unmet need to improve outcomes in those unsuitable for SCT post‐BV.
The phase III GALLIUM trial assessed the safety and efficacy of obinutuzumab‐based versus rituximab‐based immunochemotherapy in patients with previously untreated follicular lymphoma (FL) or marginal ...zone lymphoma (MZL). At the primary analysis, the trial met its primary end point, demonstrating improvement in investigator‐assessed progression‐free survival (PFS) with obinutuzumab‐based versus rituximab‐based immunochemotherapy in patients with FL. We report the results of the final analysis in the FL population, with an additional exploratory analysis in the MZL subgroup. Overall, 1202 patients with FL were randomized 1:1 to obinutuzumab‐ or rituximab‐based immunochemotherapy followed by maintenance with the same antibody for up to 2 years. After a median 7.9 (range, 0.0–9.8) years of follow‐up, PFS remained improved with obinutuzumab‐ versus rituximab‐based immunochemotherapy, with 7‐year PFS rates of 63.4% versus 55.7% (P = 0.006). Time‐to‐next antilymphoma treatment was also improved (74.1% versus 65.4% of patients had not started their next antilymphoma treatment at 7 y; P = 0.001). Overall survival was similar between the arms (88.5% versus 87.2%; P = 0.36). Irrespective of the treatment received, PFS and OS were higher in patients with a complete molecular response (CMR) versus those with no CMR (P < 0.001). Serious adverse events were reported in 48.9% and 43.4% of patients in the obinutuzumab and rituximab arms, respectively; there was no difference in the rate of fatal adverse events (4.4% and 4.5%, respectively). No new safety signals were reported. These data demonstrate the long‐term benefit of obinutuzumab‐based immunochemotherapy and confirm its role as a standard‐of‐care for the first‐line treatment of advanced‐stage FL, taking into account patient characteristics and safety considerations.
Standard-of-care treatment for patients with newly diagnosed multiple myeloma is bortezomib-based induction followed by high-dose melphalan and autologous haematopoietic stem-cell transplantation ...(HSCT) and lenalidomide maintenance. We aimed to evaluate whether an immunomodulatory-free carfilzomib-based induction, consolidation, and maintenance protocol without autologous HSCT was non-inferior to the same induction regimen followed by autologous HSCT and maintenance.
CARDAMON is a randomised, open-label, phase 2 trial in 19 hospitals in England and Wales, UK. Newly diagnosed, transplantation-eligible patients with multiple myeloma aged 18 years or older with an Eastern Cooperative Oncology Group (ECOG) performance status of 0–2 received four 28-day cycles of carfilzomib (56 mg/m2 intravenously on days 1, 2, 8, 9, 15, and 16), cyclophosphamide (500 mg orally on days 1, 8, and 15), and dexamethasone (40 mg orally on days 1, 8, 15, and 22; KCd), followed by peripheral blood stem cell mobilisation. Patients with at least a partial response were randomly assigned (1:1) to either high-dose melphalan and autologous HSCT or four cycles of KCd. All randomised patients received 18 cycles of carfilzomib maintenance (56 mg/m2 intravenously on days 1, 8, and 15). The primary outcomes were the proportion of patients with at least a very good partial response after induction and difference in progression-free survival rate at 2 years from randomisation (non-inferiority margin 10%), both assessed by intention to treat. Safety was assessed in all patients who started treatment. The trial is registered with ClinicalTrials.gov (NCT02315716); recruitment is complete and all patients are in follow-up.
Between June 16, 2015, and July 8, 2019, 281 patients were enrolled, with 218 proceeding to randomisation (109 assigned to the KCd consolidation group 99 of whom completed consolidation and 109 to the HSCT group 104 of whom underwent transplantation). A further seven patients withdrew before initiation of carfilzomib maintenance (two in the KCd consolidation group vs five in the HSCT group). Median age was 59 years (IQR 52 to 64); 166 (59%) of 281 patients were male and 115 (41%) were female. 152 (71%) of 214 patients with known ethnicity were White, 37 (17%) were Black, 18 (8%) were Asian, 5 (2%) identified as Mixed, and 2 (1%) identified as other. Median follow-up from randomisation was 40·2 months (IQR 32·7 to 51·8). After induction, 162 (57·7%; 95% CI 51·6 to 63·5) of 281 patients had at least a very good partial response. The 2-year progression-free survival was 75% (95% CI 65 to 82) in the HSCT group versus 68% (95% CI 58 to 76) in the KCd group (difference –7·2%, 70% CI –11·1 to –2·8), exceeding the non-inferiority margin. The most common grade 3–4 events during KCd induction and consolidation were lymphocytopenia (72 26% of 278 patients who started induction; 15 14% of 109 patients who started consolidation) and infection (50 18% of 278 for induction; 15 14% of 109 for consolidation), and during carfilzomib maintenance were hypertension (20 21% of 97 patients in the KCd consolidation group vs 23 23% of 99 patients in the HSCT group) and infection (16 16% of 97 patients vs 25 25% of 99). Treatment-related serious adverse events at any point during the trial were reported in 109 (39%) of 278 patients who started induction, with infections (80 29%) being the most common. Treatment-emergent deaths were reported in five (2%) of 278 patients during induction (three from infection, one from cardiac event, and one from renal failure) and one of 99 patients during maintenance after autologous HSCT (oesophageal carcinoma).
KCd did not meet the criteria for non-inferiority compared with autologous HSCT, but the marginal difference in progression-free survival suggests that further studies are warranted to explore deferred autologous HSCT in some subgroups, such as individuals who are MRD negative after induction.
Cancer Research UK and Amgen.
Background and Objectives. Attention to ovary dose is important for premenopausal women undergoing radiation therapy (RT) and must not be overlooked when treating extremity sarcoma. We assessed ...whether ovary-sparing RT plans could decrease ovary dose without compromising target coverage. Methods. Standard sarcoma target volumes and organs at risk (OAR) were contoured by a sarcoma dedicated radiation oncologist on CT planning scans for 23 women with thigh or buttock sarcoma. IMRT plans (50 Gy) with and without attempted ovary-sparing were created by an expert sarcoma dosimetrist. Results. All plans met target coverage goals. Compared to standard plans, ovary-sparing plans had lower mean bilateral ovary doses (MBOD) (652 versus 483 cGy, p=0.007) but higher bone doses (mean V50: 8.5% versus 6.9%, p=0.049) and lower conformity indexes (1.12 versus 1.19, p=0.009). Tumors < 8 cm from the pubic symphysis had significant MBOD reduction with ovary-sparing plans (376 cGy versus 619 cGy, p=0.0184). On multivariate analysis, distance to pubic symphysis and proximal medial thigh site were associated with MBOD reduction with ovary-sparing plan. Conclusions. For preoperative IMRT, ovary-sparing planning significantly reduces ovarian dose in women with sarcoma of the proximal thigh and near the pubic symphysis.
In the original version of this article, the mention of 'ifosfamide 1500 mg/m
days 1-3' should, in fact, read 'ifosfamide 1500 mg/m
bd days 1-3'. This has now been updated in the original version of ...the article.
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