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Patients with hematologic malignancies have impaired humoral immunity secondary to their malignancy and its treatment, placing them at risk of severe coronavirus disease-19 (COVID-19) infection and reduced response to vaccination.The authors retrospectively analyzed serologic responses to initial and booster COVID-19 vaccination in 378 patients with hematologic malignancy and subsequently tracked COVID-19-related outcomes.Seroconversion occurred in 181 patients (48%) after initial vaccination; patients who had active malignancy or those who were recently treated with a B-cell-depleting monoclonal antibody had the lowest rates of seroconversion. For initial nonresponders to vaccination, seroconversion after a booster dose occurred in 48 of 85 patients (56%). The seroconversion rate after the booster was similar for patients on (53%) and off (58%) active therapy (p = .82). Thirty-three patients (8.8%) developed a COVID-19 infection, and there were three COVID-19-related deaths (0.8%). Although no significant association was observed between postvaccination seroconversion and the incidence of COVID-19 infection, no patient with seroconversion died from COVID-19, and no patient who received tixagevimab/cilgavimab (N = 25) was diagnosed with a COVID-19 infection.Booster vaccinations can promote seroconversion in a significant proportion of patients who are seronegative after the initial vaccination course regardless of the specific vaccine or on/off treatment status at the time of revaccination. Although postvaccination seroconversion may not be associated with a decrease in any (including asymptomatic) COVID-19 infection, the authors' experience suggested that effective vaccination (including a booster), supplemented by passive immunization using tixagevimab/cilgavimab in case of lack of seroconversion, effectively eliminated the risk of COVID-19 death in the otherwise high-risk population.Patients with hematologic malignancy, especially lymphoma, have an impaired response to coronavirus disease 2019 (COVID-19) vaccination. In this single-institution review, less than one half of the patients studied made detectable antibodies. For those who did not make detectable antibodies after initial vaccination, over one half (65%) were able to produce antibodies after booster vaccination. By the end of February 2022, 33 of the original 378 patients had a documented COVID-19 infection. The only deaths from COVID-19 were in those who had undetectable antibodies, and no patient who received prophylactic antibody therapy developed a COVID-19 infection.

Ceramics have long held significance as a prime material to humans and today can be found in any industry. This paper discusses the successful application of standalone ceramic screens as an emerging technology solution for well restoration and sand control in Columbus Basin offshore fields. In well sand screens, they are proposed to significantly boost erosional limits and durability, when compared to traditional metallic screens. This hypothesis was tested in oil and high-rate gas wells in highly unconsolidated and low volume reservoirs which were previously shut-in or undeveloped for various reasons. In all cases, development through traditional rig-based sand control techniques would have been uneconomic. This paper presents the job design approach including candidate selection, screen selection, erosion testing, and deployment. Well performance post implementation is also examined. Initial screening for up-hole recomplete candidates showed that a sand control completion was required to access reserves from the unconsolidated reservoirs. Additionally, the proposed reservoir intervals were short and resulted in high flow velocities challenging even traditional sand control techniques such as cased hole gravel packs. Applying a ceramic standalone screen as a solution was based on the building of a natural sand pack to retain the formation sand with screen slot sizing designed to minimize plugging. Various screen slot sizes, geometries and analogous cores were tested in laboratory sand retention tests to retain the largest sand particle sizes and allow a natural sand pack to develop. Interpretation of the results was often challenging due to the wide variabilities in particle size distributions inherent to the nature of the sands being tested – non-uniform, poorly sorted and high fines content. Deployment of the screens was performed rig-less and was further complicated by aged offshore infrastructure with de-rated cranes, limited deck space and compact well bays. Bespoke solutions were developed to allow screen deployment without the use of the platform crane and straddle systems to enable downhole connection of multiple screen sections. Standalone screen designs were developed for failed sand control repairs and newly perforated sections. Start-up of the wells was performed with a bean-up strategy allowing for a stabilized natural sand pack development. Both oil and high-rate gas wells showed similar results with sand free production from the onset with minimal plugging on most applications. This paper will discuss the importance of candidate selection to minimize same. Utilizing job data and flowing measurable parameters, the ceramic screens flow velocity performance was estimated to be between five and ten times greater than those associated with traditional metallic sand screens under the same standalone application. Further laboratory erosion work was also performed to de-risk the flow rate potential of installed ceramic screens, significantly improving understanding of the failure mechanisms of the ceramic screen. This resulted in doubling previous flux velocity thresholds for the screen from 100 ft/s to 200ft/s. The performance of ceramic screens highlights their applicability as a viable sand control technique once properly aligned to expected well performance. It now widens the toolbox of non-rig sand control applications beyond the conventional rule of thumb provides a lower cost alternative to rig completions.

Prostate specific membrane antigen (PSMA) is an emerging diagnostic and therapeutic target in prostate cancer.

Background Integrated PET/MRI is a promising modality for breast assessment. The most frequently used tracer, fluorine 18 (18F) fluorodeoxyglucose (FDG), is applied for whole-body staging in advanced breast cancer but has limited accuracy in evaluating primary breast lesions. The fibroblast-activation protein (FAP) is abundantly expressed in invasive breast cancer. FAP-directed PET tracers have recently become available, but results in primary breast tumors remain lacking. Purpose To evaluate the use of FAP inhibitor (FAPI) breast PET/MRI in assessing breast lesions and of FAPI whole-body scanning for lymph node (LN) and distant staging using the ligand gallium 68 (68Ga)-FAPI-46. Materials and Methods In women with histologically confirmed invasive breast cancer, all primary 68Ga-FAPI-46 breast and whole-body PET/MRI and PET/CT examinations conducted at the authors' center between October 2019 and December 2020 were retrospectively analyzed. MRI lesion characteristics and standardized uptake values (SUVs) were quantified with dedicated software. Mann-Whitney U tests were used to compare tumor SUVs across different tumor types. The Pearson correlation coefficient was calculated between SUV and measures of MRI morphologic characteristics. Results Nineteen women (mean age, 49 years ± 9 [standard deviation]) were evaluated-18 to complement initial staging and one for restaging after therapy for distant metastases. Strong tracer accumulation was observed in all 18 untreated primary breast malignancies (mean maximum SUV [SUVmax] = 13.9 [range, 7.9-29.9]; median lesion diameter = 26 mm [range, 9-155 mm]), resulting in clear tumor delineation across different gradings, receptors, and histologic types. All preoperatively verified LN metastases in 13 women showed strong tracer accumulation (mean SUVmax= 12.2 [range, 3.3-22.4]; mean diameter = 21 mm [range, 14-35 mm]). Tracer uptake established or supported extra-axillary LN involvement in seven women and affected therapy decisions in three women. Conclusion This retrospective analysis indicates use of 68Ga fibroblast-activation protein inhibitor tracers for breast cancer diagnosis and staging. © RSNA, 2021 Online supplemental material is available for this article. See also the editorial by Mankoff and Sellmyer in this issue.

The clinical significance of collateral flow for the ventricular function of patients with univentricular hearts is often debated. This study evaluates the impact of collateral flow on respiration-dependent preload modification and diastolic function in Fontan patients assessed by systemic and pulmonary vein (PV) flow patterns.Real-time phase-contrast cardiovascular magnetic resonance was performed in the right upper PV, ascending aorta, superior, and inferior vena cava (IVC) in 21 Fontan patients and 11 healthy individuals. The patients' respiratory cycle was divided into 4 periods to generate respiratory-dependent stroke volumes (SVi). Conventional quantitative blood flow measurements were used to quantify and differentiate between low (group A) and high (group B) collateral flow.Group B showed significantly lower SVi IVC in inspiration, end-inspiration, expiration, and SVi ΔIVC compared with group A (23.6±4.8 mL/m2 to 33.4±8.0; P=0.005). PV flow resulted in a lower mean SVi PV (11.6±7.6 mL/m2, vs. 14.0±11.4 mL/m2) as well as a significantly lower peak systolic S-wave velocity (Smax) (P=0.005), S/D-ratio (Smax/peak diastolic wave velocity) (P=0.015), and shorter diastolic deceleration time (DTD; P=0.030; median DTD=134 ms) compared with group A (DTD=202 ms).This study demonstrates the incapability of Fontan patients to properly increase preload by inspiration in the presence of significant collateral flow. The results further show that collateral flow is associated with a volume-deprived ventricle and impaired diastolic function.

Monoclonal gammopathies are a spectrum of disorders characterized by the overproduction of plasma B-cells and immunoglobulin. Monoclonal gammopathy of uncertain significance (MGUS), a pre-malignant form of multiple myeloma, is defined by relatively low bone marrow concentration of clonal plasma cells and asymptomatic clinical presentation. New evidence, however, points to an association of MGUS with osteoporosis, microarchitectural bone deficiency, and fractures, and it has been suggested that it be renamed "Monoclonal Gammopathy of Skeletal Significance." The prevalence of MGUS in the general geriatric population is estimated to be 3-8%, while the prevalence in geriatric vertebral fracture patients is 15%, and the prevalence in all fracture patients within the Rhode Island Fracture Liaison Service is 10%. Therefore, MGUS and other monoclonal gammopathies should be suspected in all patients diagnosed with osteoporosis or an osteoporotic fracture, and patients diagnosed with monoclonal gammopathies should be evaluated for osteoporosis and fracture risk and treated appropriately.

Pandemic outbreaks of viruses such as influenza virus or SARS-CoV-2 are associated with high morbidity and mortality and thus pose a massive threat to global health and economics. Physiologically relevant models are needed to study the viral life cycle, describe the pathophysiological consequences of viral infection, and explore possible drug targets and treatment options. While simple cell culture-based models do not reflect the tissue environment and systemic responses, animal models are linked with huge direct and indirect costs and ethical questions.

SARS-CoV-2 is the causative agent of the immune response-driven disease COVID-19 for which new antiviral and anti-inflammatory treatments are urgently needed to reduce recovery time, risk of death and long COVID development. Here, we demonstrate that the immunoregulatory kinase p38 MAPK is activated during viral entry, mediated by the viral spike protein, and drives the harmful virus-induced inflammatory responses. Using primary human lung explants and lung epithelial organoids, we demonstrate that targeting p38 signal transduction with the selective and clinically pre-evaluated inhibitors PH-797804 and VX-702 markedly reduced the expression of the pro-inflammatory cytokines IL6, CXCL8, CXCL10 and TNF-α during infection, while viral replication and the interferon-mediated antiviral response of the lung epithelial barrier were largely maintained. Furthermore, our results reveal a high level of drug synergism of both p38 inhibitors in co-treatments with the nucleoside analogs Remdesivir and Molnupiravir to suppress viral replication of the SARS-CoV-2 variants of concern, revealing an exciting and novel mode of synergistic action of p38 inhibition. These results open new avenues for the improvement of the current treatment strategies for COVID-19.

Background Newly diagnosed multiple myeloma patients have many available treatment options. While lenalidomide, bortezomib, and dexamethasone (RVD) is the preferred initial treatment for many patients, several other agents may provide similar efficacy with less toxicity and improved ease of administration. Methods We evaluated the safety and efficacy of the all-oral regimen of ixazomib, cyclophosphamide, and dexamethasone with the use of metronomic cyclophosphamide dosing in the treatment of patients with newly diagnosed multiple myeloma. Results The study was stopped prior to planned enrollment due to slow recruitment, with 12 patients available for final analysis. The overall response rate was 58.3% with 2 patients achieving a very good partial response (16.7%) and 5 patients achieving a partial response (41.7%). Median progression-free survival was 16 months, and median overall survival was 43 months. There were no episodes of grade 3 or greater peripheral neuropathy. Grade 3 or greater dermatologic toxicity was experienced in 50% of patients. Conclusion Although limited enrollment prevented full efficacy evaluation, our data do not support further study of metronomic cyclophosphamide in combination with ixazomib and dexamethasone in the treatment of newly diagnosed multiple myeloma. The activity of this regimen in the relapsed/refractory setting requires further study (ClinicalTrials.gov Identifier: NCT02412228).

Downhole sand control selection plays a vital role in sand free production optimization over the well lifecycle. Design and selection criteria to assess the optimum sand control methodology requires consideration of many inputs to assess the sand control service life. A qualified sand control method, offering high erosion resistance is critical to enhance service life, especially in cases where small particles may be entrained in the produced fluids at high velocity. An integrated approach considering advances in filter media material, allow integration of ceramic components, to redefine operating envelope of sand control screen. In the process of designing and selecting a suitable sand control method for a high-rate gas well application in Norway, ceramic sand screens were considered as a possible solution to manage the high erosion loading expected during production. To estimate the operational limits for stand-alone ceramic sand screens, a series of erosion tests were conducted by a third party research and testing agency defined by the operator to evaluate the erosion behavior of the ceramic filter element. As indicator for erosion the filtration cut point (FCP) of the ceramic filter element was used. The testing allowed the operating envelope of the ceramic screens to be defined in terms of FCP and erosion load. For a specific increase in FCP value the operational limits for a stand-alone ceramic sand screen can estimated. This methodology was then applied to a specific field application to predict ceramic sand screen lifetime for the expected production profile. This paper presents the results of the study, using CFD simulations and, independent industry testing methodology to investigate the suitability and expected service life for stand-alone ceramic sand screen. Understanding the operational erosion risk profiling enables the operator to apply an erosional resistant stand-alone screen approach offering reducing planning, deployment complexity, lower HS&E risk and increased flexibility in optimising the wells production envelope.

The "triplet" regimen of lenalidomide, bortezomib, and dexamethasone (RVD) showed survival advantage over lenalidomide-dexamethasone (RD) in clinical trials, but older patients with myeloma often receive doublet regimens (RD or bortezomib-dexamethasone, VD), or VD plus cyclophosphamide (VCD). We compared these first-line regimens using real-world data from Medicare beneficiaries receiving therapy between 2007 and 2015. In each comparative analysis, we balanced confounding characteristics using a propensity score. Outcomes included overall (OS) and event-free survival (EFS, reporting hazard ratios [HR] with 95% confidence intervals [CI]), adverse events, and costs. We identified 6076 patients with median age 76 and median OS of 2.6 years. In the comparison of RVD vs RD/VD doublets, RVD showed significantly better OS (HR = 0.83; 95% CI, 0.72-0.95) and EFS (HR = 0.68; 95% CI, 0.61-0.76). So, RVD was associated with more frequent hospitalizations, anemia, and neuropathy, but no increase in thromboembolism or secondary cancers. Costs were higher with RVD. In the comparison of RD vs VD, RD demonstrated better EFS (HR = 0.74; 95% CI, 0.68-0.81) and marginally better OS (HR = 0.91; 95% CI, 0.83-0.99). And, RD resulted in significantly more thromboembolic events, less neuropathy, and no significant difference in hospitalizations, transfusions, or secondary cancers. In the comparison of VCD vs VD, we observed no significant difference in any outcome. Superior survival favors RVD over doublet regimens, but even in 2015 RVD was applied for only about 25% of Medicare beneficiaries with myeloma. For patients not eligible for RVD due to toxicity, VCD offers no survival benefit over VD. Lenalidomide-dexamethasone may be the preferred line doublet considering its advantage over VD.

The MAF translocations, t(14;16) and t(14;20), are considered as adverse prognostic factors based on few studies with small sample sizes. We report on their prognostic impact in a large group of 254 patients - 223 (87.8%) with t(14;16) and 31 (12.2%) with t(14;20). There were no intergroup differences in survival estimates. Median progression-free survival was 16.6 months for t(14;16) and 24.9 months for t(14;20) (

Virchows Archiv (2022). doi:10.1007/s00428-022-03319-2, Published by Springer, Berlin

Claudins are promising biomarkers for diagnosis and prognosis or targets for treatment. They play a major role in signal transduction and are important in nearly all aspects of tumorigenesis. Claudin 6 is a member of the claudin family and is part of the tight junction molecule. It is reactivated in several cancer types and serves as prognostic marker in, for example, gastric, breast or non small cell lung cancer. The prognostic role of Claudin 6 in renal cell carcinoma (RCC), especially in papillary RCC (pRCC), is still unclear.The patients' sample collection was a joint collaboration of the PANZAR consortium. Patients' medical history and tumor specimens were collected from n = 240 and n = 128 patients with type 1 and 2 pRCC, respectively. Expression of Claudin 6 was determined by immunohistochemistry.In total, Claudin 6 staining was positive in 55 of 240 type 1 and 30 of 128 type 2 pRCC cases. Kaplan-Meier analysis disclosed an overall survival of 84% for Claudin 6- compared to 78% for Claudin 6 + in pRCC type 1 tumors (p = 0.449, log-rank) and 68% for Claudin 6- compared to 65.4% for Claudin 6 + in pRCC type 2 tumors (p = 0.364, log-rank).In this study, claudin 6 expression showed no significant association regarding overall survival (OS) and therefore did not qualify as a prognostic marker in pRCC. Future studies will have to determine, whether Claudin 6 plays a prognostic role in other RCC entities. In addition, the function of Claudin 6 as a predictive marker for therapeutic approaches has to be evaluated in future studies.

The lancet / Regional health. Europe 15, 100330 (2022). doi:10.1016/j.lanepe.2022.100330, Published by Elsevier, [Amsterdam]

Purpose Quantitative blood flow measurements in thoracic vessels are dependent on the patient's respiration due to intrathoracic pressure changes. Several registration techniques for tracing the patient's breathing curve exist exploiting various physiological characteristics. In the presented study two registration techniques were investigated to estimate the time-shift between the associated respiration curves and the impact on respiration-dependent hemodynamic measures. Materials and methods Using flow-sensitive real-time magnetic resonance imaging (3.0 T, temporal resolution = 24–26 ms) data were acquired during a 13 s time-interval under normal physiological (no) and forced breathing (fo) in the ascending aorta (AAo) and inferior vena cava (IVC). Breathing curves were obtained by using (1) an abdominal placed respiratory belt (=standard, RB) and (2) by applying a self-developed edge-detection software (ED). Respiration curves were divided into four intervals (end-expiration, inspiration, end-inspiration and expiration) to generate respiration-dependent stroke volumes (SVs) and cardiac indices (CIs). Data were available from 12 healthy controls (16.2 ± 8.8 yrs) and 18 Fontan-patients (18.6 ± 7.1 yrs). Results Respiration curves acquired with RB differs from and are shifted compared to those obtained by ED (controls: average shift = 207 ± 168 ms, Fontan-patients: average shift = 106 ± 235 ms). This time-shift results in statistical significant differences in cardiac indices CIAAo,fo in controls (ΔCIAAo,fo: expiration: +0.16 L/min/m2, p = 0.018), in CIIVC,no in Fontan-patients (ΔCIIVC,no: end-expiration: +0.94 L/min/m2, p = 0.002 and end-inspiration: −1.04 L/min/m2, p = 0.017) and in CIIVC,fo in Fontan-patients (ΔCIIVC,fo: end-expiration: +1.31 L/min/m2, p = 0.009; inspiration: −2.26 L/min/m2, p = 0.008 and end-inspiration: −1.87 L/min/m2, p = 0.029). Conclusions A time-shift between both applied respiratory tracking techniques was observed resulting in significant differences in respiration-dependent CIs, which could influence the clinical decision-making.

Papillary renal cell carcinoma (PRCC) is currently divided in 2 subtypes. We reviewed a large cohort of PRCC and correlated subtype, morphological features and diagnostic marker expression with overall survival (OS) to uncover differences between the 2 subtypes. Three hundred seventy-six renal tumors initially diagnosed as PRCC with clinical and survival data were collected from the participating centers. Two hundred forty-six tumors were classified as PRCC1 (65.4%) and 130 as PRCC2 (34.6%) and graded according to the 2016 World Health Organization/International Society of Urological Pathology grading system. Morphological features (abundant cytoplasm, necrosis, fibrous stroma, foamy macrophages and psammoma bodies) were noted. Immunohistochemical stains (MIB1, p53, Racemase, EMA, CK7, CK20, E-Cadherin) were performed using tissue microarrays. χ2-Tests, log-rank tests and uni- and multivariate Cox regression analysis were performed. Both subtypes displayed different morphological features and immunohistochemical profiles: abundant cytoplasm was more frequent in PRCC2, while foamy macrophages were more common in PRCC1. Abundant cytoplasm and presence of psammoma bodies were associated with poorer OS. PRCC1 showed more frequent CK7 expression, PRCC2 more frequent E-Cadherin, p53 and higher MIB1 expression (>15%). Expression of Racemase and CK7 was associated with better OS, while high MIB1 (>15%) was associated with poorer OS. In multivariate analysis, the only independent predictors of OS were proliferation (MIB1), tumor stage, metastasis and age at surgery. Subtype was not an independent prognostic factor. Therefore, PRCC subtype on its own is not suitable for estimating survival. More data focusing on PRCC tumor biology is needed to define prognostic subgroups, especially in PRCC2.

Zusammenfassung Hintergrund Die antineoplastische Wirkung intravesikal applizierter, immunstimulatorischer CpG-Oligodesoxynukleotide in einem murinen, orthotopen Urothelzellkarzinom-Modell (C57-BL-6 /MB49) konnte bereits wiederholt nachgewiesen werden. Nach wie vor sind jedoch viele Details der Wirkweise ungeklärt. Vorangegangene Untersuchungen weisen in Richtung einer zellulären, Th1-gewichteten Immunantwort. Die vorliegende Arbeit hat zum Ziel, mit immunhistologischen Techniken einerseits das lymphozytäre Infiltrat im behandelten Blasengewebe zu subklassifizieren, andererseits den Effekt einer topischen CpG-ODN-Konfrontation auf die Expression von ICAM-1, eines für die zelluläre Immunantwort essenziellen Oberflächenmoleküls, zu untersuchen. Material und Methoden In einem etablierten, murinen, orthotopen UCC-Modell kamen verschiedene Instillationschemata von CpG-ODN zur Anwendung. Nach 13 Tagen wurden Gefrierschnitte der entnommenen Blasen angefertigt und immunhistochemisch auf Infiltrationsdichte CD3-, CD4-, CD8- und CD 19- exprimierender Lymphozyten untersucht. In einer zweiten Versuchsreihe am selben Tiermodell wurden gesunde und tumortragende Blasen instillativ mit CpG-ODN oder PBS behandelt und anschließend gegen das interzelluläre Adhäsionsmolekül 1 (ICAM-1) gefärbt. Ergebnisse Die CpG-ODN-Instillation führt zu einer erhöhten T-Zellinfiltration. Eine weitere Subdifferenzierung zwischen T-Helfer-Zellen (CD4) und zytotoxischen T-Zellen (CD8) erbrachte keine Unterschiede zwischen den verschiedenen Gruppen in Abhängigkeit vom Instillationsschema. Eine rückläufige B-Zellinfiltration im Laufe der Therapie wurde beobachtet.Zusätzlich führt die CpG-ODN-Behandlung zu einer vermehrten Expression von ICAM-1 sowohl auf interstitiellen Leukozyten als auch Endothelien und insbesondere auf den Tumorzellen selbst. Diskussion Die bereits in früheren Untersuchungen beobachtete vermehrte Lymphozytendichte konnte einem T-Zellinfiltrat zugeordnet werden. Die mit zunehmender Therapiedauer abnehmende B-Zelldichte spricht für eine Unterdrückung der Th2-Antwort zugunsten einer Th1-Polarisierung. Diese Ergebnisse stützen die These einer zellvermittelten Immunantwort als grundliegendem Mechanismus der antineoplastischen CpG-ODN-Wirkung. Die deutliche Steigerung der ICAM-1 Expression, vor allem auf den Tumorzellen, legt eine Schlüsselfunktion dieses Oberflächenmoleküls in der Einleitung und Aufrechterhaltung der antineoplastischen Immunantwort nahe. Schlussfolgerung CpG-ODN könnten perspektivisch eine Alternative zu den gängigen Instillationstherapeutika darstellen. Mit Blick auf die aktuellen BCG-Engpässe und die erheblichen Nebenwirkungen ist eine Erweiterung des adjuvanten, topisch anwendbaren Armamentariums möglich. Das in dieser Arbeit erstmals gezeigte Potential einer Induktion der ICAM-1 Expression und damit einer Umkehr von Immune-Escape-Strategien solider Tumoren macht die Substanz aber auch als Adjuvanz einer modernen Checkpoint-Inhibition interessant.

Introduction: Treatment of relapsed and refractory multiple myeloma (RRMM) continues to evolve as most patients are lenalidomide (LEN) refractory at the time of first relapse with its widespread use in both induction and maintenance therapy. Pomalidomide, bortezomib and dexamethasone in RRMM has demonstrated significant activity and improvement in progression-free survival in LEN-refractory patients (Richardson et al Lancet Oncol 2019 Jun;20(6):781-794). Ixazomib is a novel oral proteasome inhibitor (PI) that is currently approved in combination with LEN and dexamethasone in RRMM. Ixazomib is administered on a once weekly schedule and its oral route of administration is particularly attractive, not least in the context of the current COVID-19 pandemic. Twice weekly dosing of ixazomib has been studied in combination with LEN demonstrating promising activity in NDMM (Richardson et al, Br J Haematol. 2018 Jul;182(2):231-244). Moreover, safety and efficacy has been shown in RRMM as twice weekly monotherapy on this schedule (Richardson et al, Blood 2014 Aug 14;124(7):1038-46). We hypothesized that a twice weekly ixazomib schedule in combination with pomalidomide and dexamethasone will lead to enhanced efficacy and comparable safety in RRMM. Methods: This is a phase I/II multicenter, single-arm, open label study evaluating the combination of twice weekly ixazomib with pomalidomide and dexamethasone in RRMM. Primary objective for phase I portion is to determine safety and the maximum tolerated dose (MTD) of this combination using a standard 3+3 dose escalation design. Ixazomib is studied at doses of 3mg or 4mg on days 1, 4, 8, 11, pomalidomide at a dose of 2mg, 3mg and 4mg on days 1-14 and dexamethasone is administered at a dose of 12mg on days 1, 2, 4, 5, 8, 9, 11, 12 (8mg for patients > 75 years old) on a 21 day cycle (Table 1). Patients were included if they received 2 prior lines of therapy, but 1 prior line was allowed if first line treatment included a PI and an immunomodulatory agent and disease relapse occurred within 60 days of last therapy. Patients who received prior ixazomib were excluded. Results: At the time of data cutoff, 12 patients have been enrolled across cohorts 0, 1 and 2 and enrollment in the final cohort 3 is ongoing. Median age at the time of enrollment was 70 years old with slight male predominance (58%). ISS stage at diagnosis was II or greater in 75% of patients and 9 out of 12 (75%) patients had high-risk FISH as follows: del 17p (17%), gain 1q (50%), and t(4;14) (8%). Median prior lines of therapy was 2 (range 1-3) with 100% of patients having prior treatment with lenalidomide and 92% with prior bortezomib. Forty-two percent of patients had a prior autologous stem cell transplant. Most common treatment-related toxicities were mainly low grade and included neutropenia (58%), hyperglycemia (42%), fatigue (33%), anemia (25%), thrombocytopenia (25%), and rash (25%). Grade 3 or greater toxicities included neutropenia (17%), anemia (8%), bacterial lung infection (8%), and atrial fibrillation (8%). There was 1 dose limiting toxicity (DLT) in cohort 2 due to lung infection necessitating a delay in initiation of cycle 2 and no further DLTs have been noted. Dose reductions occurred in 4 patients and predominantly involved dexamethasone due to weight gain, insomnia, atrial fibrillation and fatigue. There have been no discontinuations due to toxicity and no treatment related mortality at the time of data cutoff. In response evaluable patients, 5 out of 12 patients have demonstrated a partial response or better (42%), with 1 very good partial response (VGPR) and all patients at least achieving stable disease. Conclusions: Twice weekly ixazomib in combination with pomalidomide and dexamethasone is a generally well-tolerated regimen with promising early activity in a high-risk RRMM cohort. Maximal tolerated dose and recommend phase II dose has not yet been reached and this study continues to accrue robustly, reflecting in part the convenience and safety of an all oral approach in the current era of COVID-19. Moreover, the ability to perform remote laboratory testing, telemedicine visits and to send medications directly to patients has been an additional value-add to this trial. Updated data will be presented at the meeting. Disclosures Nadeem: Sanofi: Consultancy, Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees; Adaptive: Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: TRAVEL, ACCOMMODATIONS, EXPENSES; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: TRAVEL, ACCOMMODATIONS, EXPENSES. Mo:Celgene: Membership on an entity's Board of Directors or advisory committees. Barth:Sanofi: Membership on an entity's Board of Directors or advisory committees. Sanchorawala:Takeda: Research Funding; Celgene: Research Funding; Prothena: Research Funding; Caelum: Research Funding; Oncopeptide: Research Funding; Regeneron: Other: advisory board; Caleum: Other: advisory board; Proclara: Other: advisory board; Abbvie: Other: advisory board; UpToDate: Patents & Royalties; Janssen: Research Funding. Munshi:BMS: Consultancy; OncoPep: Consultancy, Current equity holder in private company, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties; C4: Current equity holder in private company; Janssen: Consultancy; Adaptive: Consultancy; Legend: Consultancy; Amgen: Consultancy; AbbVie: Consultancy; Karyopharm: Consultancy; Takeda: Consultancy. Ghobrial:Celgene: Consultancy, Honoraria; GlaxoSmithKline: Consultancy; Genentech: Consultancy; Novartis: Consultancy; Noxxon Pharma: Consultancy; Adaptive Biotechnologies: Consultancy, Honoraria; Sanofi: Consultancy, Honoraria; Cellectar: Honoraria; Karyopharm Therapeutics: Consultancy, Honoraria; GNS Healthcare: Consultancy; Janssen: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; AbbVie: Consultancy; Takeda: Consultancy, Honoraria; Bristol-Myers Squibb: Consultancy, Honoraria. Anderson:Oncopep and C4 Therapeutics.: Other: Scientific Founder of Oncopep and C4 Therapeutics.; Bristol Myers Squibb: Membership on an entity's Board of Directors or advisory committees; Sanofi-Aventis: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; Gilead: Membership on an entity's Board of Directors or advisory committees; Millenium-Takeda: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees. Richardson:Celgene/BMS, Oncopeptides, Takeda, Karyopharm: Research Funding.

The Dvalin gas field is located in the Norwegian sea on NCS and is operated by Wintershall DEA Norge. It is supported by two independent reservoir structures, Dvalin East and Dvalin West. The field was explored through wells 14S and 15S in 2010 and 2012, respectively. The field is characterized by dry gas, high CO2, high temperature (160 °C) and high pressure (SIWHP 620 bar). The targeted Garn sandstone has good reservoir quality, but with a high permeability contrast. The field development was sanctioned in 2016 and calls for a 4 well solution through a centrally located subsea template, producing gas back to the host platform Heidrun TLP 15 km away. Water depth at location is 380 m and targeted reservoirs are at 4140 m MSL (East) and 4240 m MSL (West). Production plateau rates are estimated to be approximately 106 MMscf/D (3 million std m3/d) per well where thin high-permeability zones within the Garn formation are expected to dominate the inflow. The lateral facies development is thought to be relatively homogenous throughout the field, thus S-shape wells falling off to vertical through the reservoir will ensure effective drainage. Sand failure is expected after short time of production and would increase the risk of erosion causing severe damage to well jewelry and production facilities. It has been decided to integrate sand screens as a means of downhole sand control as part of the primary lower completion design. The sand screens will offer sand control, erosion resistance, hot spotting resistance as well as robustness towards a full hole collapse during reservoir pressure depletion. As the subsea completions are carried out from a mobile drilling unit in harsh environments, protection of the sand control filter media during installation is of utmost importance. This paper will describe the selection process of sand control and qualification steps carried out to use ceramic screens as the stand-alone screen solution for successful deployment and integrity for the Dvalin field development

Formation sand production is one of the major production challenges in most of the mature fields in Malaysia. Often, failure in primary sand control equipment requires the operators to adopt through-tubing sand screens as a remedial sand control. Current remedial sand control techniques utilizing metallic through tubing sand screens experience rapid wear, forcing the operator to control sand production by beaning down wells and thereby managing sand production at surface, in worst cases wells have to be shut-in. More robust technologies replacing conventional metallic screens are required. For these applications, alternative technology with ceramic sand screens have been deployed to enable higher productivity and offer enhanced resistance against erosion. Ceramic sand screens passed through a technical qualification process at Petronas and deployed in field applications both in oil and gas producers for through tubing interventions. To date 30 well interventions have been performed in various Petronas assets of Offshore East Malaysia with mixed results. Eight screen failures were observed with longevity ranging from 2.5 days to 15 months of production after installation. On average, ceramic sand screens greatly enhanced productivity return through longer performance than the conventional through tubing metallic screens from previous deployments. However, it was both the intent of product provider and Petronas to further improve Through Tubing Ceramic Sand Screen (TTCSS) performance based on the lessons learned from these failures. The TTCSS failures were first presented in the paper: SPE 196479 MS published at SPE APOGCE October 2019, Bali, Indonesia which which focused on the failures of these first generation TTCSS screen designs. This paper describes in more detail the value driven process and collaboration steps between 3M and Petronas to improve TTCSS field performance as a methodology to increase incremental field production to further increase longevity of downhole sand control in these applications. To enable this goal, a root cause analysis process entailed involving tear down investigation, hypothesis of failure characteristics, application review and investigation analysis with tools such as CFD and laboratory testing resulting in the implementation of ceramic sand screen design enhancements to improve performance in further Petronas deployments.

Formation sand production is one of the major production challenges in most of the mature fields in Malaysia. Often, failure in primary sand control equipment requires the operators to adopt through-tubing sand screens as remedial sand control. Due to the erosion prone nature of the thru-tubing metallic sand screen, operators are forced to impose limitation on the production rate coupled with stringent surface sand monitoring system to avoid surface flow line leakage and loss of primary pressure containment. Therefore, to seek a more robust technology than conventional metallic screens, alternative technology with through-tubing ceramic sand screen (TTCSS) has been considered with the idea of higher durability and resistance against erosion. This paper will discuss the performance and lessons learnt from the application of through-tubing ceramic sand screen throughout several mature fields in Offshore East Malaysia. Over the past two years, there have been about twenty-five TTCSS installations in Offshore East Malaysia. Seven pre-mature failure cases were observed, where sands were produced to the surface and even caused leaks on the flow line. The average effective production period for all TTCSS across all the fields ranges from 6 to 11 months. Teardown investigations have been conducted to diagnose the failure root cause. Most failed TTCSS exhibited similar failure patterns at the end caps, which house the spring compensator. Failure to stop the flow through the end caps led to substantial erosion at spring compensator and base pipe, inducing large flow path for sand production to the surface. Other than the design failure, application failure was observed at the ceramic rings due to their brittleness. Computational fluid dynamic simulation and laboratory testing have been conducted at the higher incremental production rates to support the observations from teardown inspections, refine the hypothesis of failure mechanism and enable an incremental design change to be modified into TTCSS. In order for TTCSS to be one of the competent candidates for remedial sand control, new improved standard design of TTCSS with strengthened end cap area will be studied to prevent similar failure.

The Belida field is an offshore field located in Block B of Indonesia’s South Natuna Sea. This field was discovered in 1989. Both oil and gas bearing reservoirs are present in the Belida field in the Miocene Arang, Udang and Intra Barat Formations. Within the middle Arang Formation, there are three gas pay zones informally referred to as Beta, Gamma and Delta. These sand zones are thin pay zones which need to be carefully planned and economically exploited. Due to the nature of the reservoir, sand production is a challenge and requires downhole sand control. A key challenge for sand control equipment in this application is erosion resistance without inhibiting productivity as high gas rates and associated high flow velocity is expected from the zones, which is known to have caused sand control failure. To help achieve a cost-effective and easily planned deployment solution to produce hydrocarbons, a rigless deployment is the preferred method to deploy downhole sand control. PSD analysis from the reservoir zone suggested from ‘Industry Rules of Thumb’ a conventional gravel pack deployment as a means of downhole sand control. However, based on review of newer globally proven sand control technologies since adoption of these ‘Industry Rules of Thumb’, a cost-effective solution could be considered and implemented utilizing Ceramic Sand Screen technology. This paper will discuss the successful application at Block B, Natuna Sea using Ceramic Sand Screens as a rigless intervention solution addressing the erosion / hot spotting challenges in these high rate production zones. The erosion resistance of the Ceramic Sand Screen design allows a deployment methodology directly adjacent to the perforated interval to resist against premature loss of sand control. The robust ceramic screen design gave the flexibility required to develop a cost-effective lower completion deployment methodology both from a challenging make up in the well due to a restrictive lubricator length to the tractor conveyancing in the well to land out at the desired set depth covering the producing zone. The paper will overview the success of multi-service and product supply co-operation adopting technology enablers to challenge ‘Industry Rules of Thumb’ replaced by rigless reasoning as a standard well intervention downhole sand control solution where Medco E&P Natuna Ltd. (Medco E&P) faces sand control challenges in their high deviation, sidetracked well stock. The paper draws final attention to the hydrocarbon performance gain resulting due to the ability for choke free production to allow drawing down the well at higher rates than initially expected from this zone.