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In coal mining it is important to know if localised areas of coal have been rendered worthless through direct contact with volcanic intrusions. To avoid dilution, accurate coked coal boundaries are...

Background: Post-transplantation cyclophosphamide (PTCy) is widely used for graft-versus-host-disease (GVHD) prophylaxis after hematopoietic cell transplantation (HCT). However, the standard PTCy dose (50 mg/kg/day) and timing (given on days +3 and +4) were largely extrapolated from murine skin allografting models, and these have never been rigorously tested to determine if they are optimal. We have shown in murine HCT models that an intermediate PTCy dose of 25 mg/kg/day on days +3/+4 is superior at preventing severe GVHD compared with 50 mg/kg/day on days +3/+4 (Wachsmuth et al., JCI. 2019). Furthermore, PTCy 25 mg/kg/day given on day +4 alone is equivalent to 25 mg/kg/day given on days +3/+4 at preventing severe GVHD (Wachsmuth et al. BBMT. 2019). Thus, the standard clinical dosing may be higher than necessary and potentially come at the cost of increased toxicity, delayed engraftment, and impaired immune reconstitution. Methods: This is a single institutional prospective phase I/II study (NCT03983850) to de-escalate PTCy exposure for adult patients with hematologic malignancies. All patients received myeloablative conditioning with IV daily busulfan/fludarabine, HLA-haploidentical bone marrow, and GVHD prophylaxis with PTCy (dose and timing based on Dose Level (DL)), mycophenolate mofetil (days +5 to +35), and sirolimus (days +5 to +80). The first 5 patients received PTCy 50 mg/kg/day on days +3/+4 (standard dosing, Dose Level 1) for comparative data. This was followed by a 3+3 dose de-escalation design testing 25 mg/kg/day on days +3/+4 (experimental, Dose Level 2) and 25 mg/kg on day +4 only (experimental, Dose Level 3), followed by a phase II expansion cohort at the better experimental dose level. The primary endpoint and dose limiting toxicity for the dose de-escalation was grade III-IV acute GVHD. Results: Phase I enrolled 19 patients, and the phase II expansion has enrolled 13 of 14 patients, 9 of whom have sufficient follow-up (60 days) to be considered evaluable for the primary endpoint; median follow-up of survivors evaluable for the primary endpoint is 288 (range 60-676) days. Patient and disease characteristics and outcomes for these patients are summarized in Table 1. No grade III-IV acute GVHD was seen at either experimental DL, and there have been no cases of grade II-IV acute GVHD at DL2 (Figure 1). Based on more reliable early engraftment (see below) but less intense and shorter duration of engraftment fevers, DL2 was taken to phase II. Engraftment was faster at the experimental DLs but was most consistent with DL2. Median neutrophil engraftment was at day 14 at DL2 compared with day 19 at the standard dosing (p=0.0004) (Figure 2A). Median platelet engraftment was at day 23 at DL2 compared with day 33 at the standard dosing (p=0.026) (Figure 2B). Correspondingly, transfusional requirements were lessened with DL2 (Figure 2C-D). Engraftment syndrome, manifesting as fever, rash, and mild transaminitis, occurred in 1 patient at DL2 and 2 patients at DL3, but resolved rapidly without intervention in all cases. Primary graft failure was seen in 1 patient at DL2, and relapse prior to engraftment was seen in 1 patient at DL3. Mucositis was less severe and shorter in duration for both experimental DLs when compared with standard PTCy dosing (Figure 2E). CMV reactivation requiring pre-emptive therapy was less frequently seen after lower PTCy dosing (Figure 3A). Symptomatic BK virus-associated cystitis in at-risk patients was shorter in duration for patients receiving lower PTCy; median duration was 74 days for the standard DL versus 26 days at DL2 and 7 days at DL3 (Figure 3B). At DL2, there have been 3 cases to date of chronic GVHD requiring systemic immunosuppression among the 13 engrafting patients with at least 100 days of follow-up. Conclusions: De-escalating PTCy exposure is feasible and effective in maintaining protection against severe acute GVHD while promoting more rapid engraftment and less early post-transplant toxicity. Two-day dosing of 25 mg/kg/day PTCy appears to allow for more consistent early engraftment and protection against protracted engraftment fevers compared with day +4 only. Longer follow-up and comparative studies are needed to understand if de-escalated PTCy is superior to the standard dosing schedule. Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare. OffLabel Disclosure: The use of cyclophosphamide as graft-versus-host disease prophylaxis

Allogeneic HCT recipients may develop BK virus (BKV)-associated hemorrhagic cystitis (BKV-HC), typically early after engraftment. Yet, BKV levels in urine and blood are not routinely monitored pre- or post-HCT. Among HCT recipients with primary immunodeficiency diseases (n=40), we prospectively monitored BKV levels by quantitative PCR in blood and urine pre-HCT, as well as weekly post-HCT through day +100 on NCT02579967. Thirty patients were considered at-risk for BKV-HC based on BKV detection in urine/blood at any timepoint. Of these, 22 (73%) developed BKV-HC. Of recipients treated on the reduced-intensity conditioning (RIC) busulfan-containing arms of the trial, 22 of 27 (81%) at-risk patients developed BKV-HC (Fig 1). By contrast, on the non-myeloablative conditioning arms, identical to RIC except for the absence of busulfan (Fig 2), 0 of 3 at-risk patients developed BKV-HC (p=0.01). No patients received antiviral or cellular therapies for BKV-HC, although 3 received cidofovir and/or brincidofovir for adenovirus infection. Three required continuous bladder irrigation; 1 required multiple cystoscopies for clot evacuation but no intravesicular therapy. Disease outside the bladder was rare: 1 patient (Fig 1 - P36, with notably atypical pattern of BKV levels in relation to symptoms) developed tissue-proven BKV nephropathy, along with radiographic and cytopathologic (SV40+ cells on bronchoalveolar lavage) evidence of BKV pneumonitis; thus, further evaluation for extravesicular disease, particularly in those without significant gross hematuria, is under way. Patient discomfort and supportive care needs were significant, especially during gross hematuria (n=19; median duration 21 days, range 2-41; see Fig 1). With neutrophil engraftment at median day +17 (range 13-42), median onset of BKV-HC symptoms was day +22 (range +5-74), with median duration of 26 days (range 6-145 days). Starting on day +21, the trajectory of urine BKV levels diverged between RIC-HCT recipients with or without BKV-HC (Fig 3), with significantly higher BKV in urine at day +28 for BKV-HC patients, median 8.98 log10 IU/mL, compared to those without, median 4.99 log10 IU/mL, Mann-Whitney p=0.02. At BKV-HC onset, median level of BKV in urine was 9.66 log10 IU/mL (range 6.01 to >9.81) and, at full resolution, 8.39 log10 IU/mL (range 2.87 to >9.81). Swimmer's plot (Fig 1) shows the peak in urine BKV to occur soon before or early into symptom onset in most and that blood BKV peak levels vary more in timing. In conclusion, in this cohort, the use of busulfan seems to be an important co-factor in BKV-HC risk, as also noted by others. The trajectory of BKV levels in urine differed between those with and without BKV-HC, although the identification of early BKV-HC predictors is limited by the short interval between divergence in case/control values and symptom onset.

It is now possible to invert frequency and time domain data to recover 3D conductivity models. The San Nicolas deposit makes an ideal test site because much is known about the deposit and also many different types of survey data have been collected there. In particular DC resistivity, 3D controlled source frequency domain data, and UTEM data have been acquired. We have inverted each of these data sets. In this talk we describe the data sets and the methodologies for inversion and compare the resultant models. The DC resistivity data were not able to see the deposit because of the conductive overburden, but both the frequency and time domain inversions produced a good image of the primary mineralized zone.

the goal of geophysical inversion is to recover a model (or suite of models) from some set of observations d. It is often the case that the inverse problem of equation 1 is ill-posed, and solutions must be regularized. Additionally, the data image d is usually contaminated by noise. To overcome these difficulties, the inverse problem is formulated as an optimization problem in which an estimate mrec of the true model m is obtained by minimizing the penalty function

lectrical conductivity is a diagnostic physical property for a variety of problems in mineral and hydrocarbon exploration. In mineral exploration, it can sometimes be related directly to the sought mineralization or it can be used to delineate geologic structure associated with the deposit. In oil exploration, conductivity can be a direct hydrocarbon indicator. One of the main impediments to using electromagnetic (EM) surveys is the complexity of the data. Unlike gravity or magnetic surveys, where the data can sometimes be used to infer geology or possibly to identify drill targets, EM data images are complex and are not connected with geology in a simple way. Over the last few years, however, we have developed computer algorithms to invert controlled source EM (CSEM) data. This opens the door for enhanced applications and for re-assessment of how data are collected and interpreted. The purpose of this article is to illustrate these ideas by applying our inversion techniques to synthetic and field data relevant to resource exploration. We begin with some background about EM surveys and our forward modelling. In an EM survey, the transmitter, or source, can be a grounded dipole or a loop which carries a time varying current. The measurements can be an electric field (E), a magnetic field (H) or its time derivative (dH/dt). The governing equations are those of Maxwell and the data are dependent upon three physical properties: electrical conductivity, magnetic permeability, and electrical permittivity. In this article we neglect the effects of electrical permittivity and assume that magnetic permeability is equal to that of free space. We concentrate upon the electrical conductivity, σ (or its reciprocal, resistivity, ρ), which, as illustrated by Table 1, varies by many orders of magnitude in earth rocks and minerals.