Citations

Abstract Abstract 169 The Philadelphia positive (Ph+) arm of the international adult acute lymphoblastic leukaemia (ALL) trial UKALL12/ECOG2993 opened in 1993 and is the largest single study of patients with Ph+ ALL, with a total of 441 participants. The first cohort of study patients was treated prior to Imatinib (N=266 “Pre Imatinib“) with 2 phases of induction therapy given over 2 months followed by matched sibling or unrelated donor myeloablative allogeneic haematopoietic stem cell transplant (alloHSCT) whenever possible. The treatment protocol and outcome for these patients has been published (Fielding et al, Blood 2009). Beginning March 2003, a second cohort of study patients had Imatinib 600mg daily added, as a consolidation block after the second induction chemotherapy, (N=86, “Late Imatinib”). From late 2005, a final cohort within the trial were given Imatinib earlier, in conjunction with the second phase of induction (N=89, “Early Imatinib”). Patients in both Imatinib cohorts resumed the drug for a further 2 years following alloHSCT, if tolerated. If alloHSCT was not possible, Imatinib was permitted for 2 years, with maintenance. The trial closed to recruitment in December 2006 (USA) and October 2008 (UK). All except 8 patients have now completed therapy. An earlier analysis of these data did not indicate a clear long-term advantage to receiving Imatinib. We now report 3-year follow-up, which shows large outcome differences between the 3 groups. There were no pre-existing differences between the 3 cohorts in terms of gender, presenting white blood cell counts and presence of central nervous system disease at diagnosis. However, the Pre-Imatinib cohort was younger than the two Imatinib cohorts, due to an increase in the upper age limit for study entry. Percentage complete remission (CR) rates and survival of induction therapy are shown in table 1. The total CR rate for the imatinib cohorts was significantly higher than for the pre-imatinib cohort (p=0.004). Table 1 Pre-Imatinib With Imatinib N=266 Total With Imatinib N=175 Part 1 Late Imatinib N=86 Part 2 Early Imatinib N=89 Died in induction<d56 5 5 3 7 Survived induction but never achieved remission 13 3 5 1 Total not achieving CR 18 8 8 8 CR on protocol induction 67 77 73 80 Total CR rate (includes those achieving remission later than post induction) 82 92 92 92 Pre- Imatinib, only 28% of patients went on to receive alloHSCT as per protocol. With any Imatinib, 44% of patients received alloHSCT as per protocol. Survival outcomes of patients in the 3 cohorts are shown in the table 2. Overall survival (OS), event free survival (EFS) and relapse free survival (RFS) are all at 3 years with 95% confidence intervals (CI) shown in brackets. The P values are for two comparisons - ** denotes the comparison between patients receiving any Imatinib and patients receiving none and ^ denotes the comparison between the Early and Late Imatinib cohorts. Table 2 Pre-Imatinib With Imatinib Total With Imatinib Part 1 Late Imatinib Part 2 Early Imatinib % OS (95% CI) (see also Figure 1) 25 (20–30) 42 (34–49) 34 (24–44) 48 (36–60) p=0.0001** p=0.05^ % EFS (95% CI) 19 (14–24) 36 (29–44) 29 (19–38) 45 (34–56) p=0.0001** p=0.04^ % RFS (95% CI) 36 (28–43) 54 (45–63) 45 (33–57) 62 (50–75) p=0.0001** p=0.02^ Figure 1 Three-year OS for patients who received per protocol alloHSCT was 59% vs. 28% (with no plateau on the curve) for those who did not receive alloHSCT as per protocol. By comparison, pre-imatinib, 5 year OS was 40% for transplanted- and 19% for non-transplanted patients. Hence, the extent to which Imatinib without subsequent alloHSCT can improve the outcome for adult Ph+ ALL is not yet clear. Figure 1. Three-year OS for patients who received per protocol alloHSCT was 59% vs. 28% (with no plateau on the curve) for those who did not receive alloHSCT as per protocol. By comparison, pre-imatinib, 5 year OS was 40% for transplanted- and 19% for non-transplanted patients. Hence, the extent to which Imatinib without subsequent alloHSCT can improve the outcome for adult Ph+ ALL is not yet clear. In conclusion, receiving any Imatinib during induction for Ph+ ALL significantly enhances CR rate and increase alloHSCT rate. This translates into a highly significant EFS, OS and RFS advantage to receiving Imatinib during therapy. An earlier start to Imatinib is significantly better than a later start. Though comparisons between study cohorts are not randomised, the large differences seen are unlikely to be explained by factors other than treatment. There can be no basis for omitting Imatinib from the initial therapy of adult patients with Ph+ ALL. However, our data show that the best outcome is seen when patients receive Imatinib followed by myeloablative alloHSCT, where nearly 60% of such patients survive 3 years from diagnosis. Disclosures: Goldstone: Roche: Honoraria, Speakers Bureau.

Abstract Abstract 2203 Background: Thrombotic thrombocytopenic purpura (TTP) is frequently characterized by severe ADAMTS13 deficiency, the cause of which is unknown. An important exception is ticlopidine-associated TTP (tc-TTP), the most common drug-induced TTP syndrome. In 1998, a possible association of TTP with ticlopidine was reported. In 1999, two additional series reported this association. In 2000, a fourth study reported severe A DAMTS13 deficiency among six of seven tc-TTP persons- suggesting a causal pathway. All of these reports were from the United States. Recently, we reported characteristics of 186 acquired idiopathic (ai)- TTP patients in Japan with severe ADAMTS13 deficiency, noting that clinical and laboratory findings for ai-TTP patients in Japan differed from those for cohorts of ai-TTP patients in Europe and North America- raising concern that TTP findings vary by region of the world. (PLOS One 2011) We now on report clinical and laboratory characteristics of a cohort of TTP patients from Japan with tc-TTP, and compare these findings to three cohorts of tc-TTP in the United States and one cohort of ai-TTP patients from Japan. Methods: We queried a database of thrombotic microangiopathy patients identified from a national TTP referral laboratory in Japan of cases identified between 1998 and 2008. Severe ADAMTS13 deficiency was characterized by activity levels < 5%. All tc-TTP patients and 186 of 911 ai-TTP patients in the database had severe ADAMTS13 deficiency and first onset of TTP. Comparisons were made to tc-TTP patients reported previously from the United States. Results: Characteristics of ai- TTP with severe ADAMTS13 deficiency in Japan and tc-TTP in Japan and US Conclusions: These data from Japan validate insights about tc-TTP initially proposed in 1998, 1999, and 2000 in the United States. Ticlopidine is a likely cause of TTP, the mechanism is via a cross-reactive antibody to ADAMTS13:AC resulting in formation of an ADAMTS13:INH, and therapeutic plasma exchange is necessary for treatment. Disclosures: Ortel: Eisai: Research Funding; Glaxo SmithKline: Research Funding; Pfizer: Research Funding; Instrumentation Laboratory, Inc: Consultancy, Research Funding; Boehringer Ingelheim: Consultancy. Fujimura:Baxter BioScience: Membership on an entity's Board of Directors or advisory committees; Alexion Pharma: Membership on an entity's Board of Directors or advisory committees.

Bleeding after cardiac surgery is a common and serious complication leading to transfusion of multiple blood products and resulting in increased morbidity and mortality. Despite the publication of numerous guidelines and consensus statements for patient blood management in cardiac surgery, research has revealed that adherence to these guidelines is poor, and as a result, a significant variability in patient transfusion practices among practitioners still remains. In addition, although utilization of point-of-care (POC) coagulation monitors and the use of novel therapeutic strategies for perioperative hemostasis, such as the use of coagulation factor concentrates, have increased significantly over the last decade, they are still not widely available in every institution. Therefore, despite continuous efforts, blood transfusion in cardiac surgery has only modestly declined over the last decade, remaining at ≥50% in high-risk patients. Given these limitations, and in response to new regulatory and legislature requirements, the Society of Cardiovascular Anesthesiologists (SCA) has formed the Blood Conservation in Cardiac Surgery Working Group to organize, summarize, and disseminate the available best-practice knowledge in patient blood management in cardiac surgery. The current publication includes the summary statements and algorithms designed by the working group, after collection and review of the existing guidelines, consensus statements, and recommendations for patient blood management practices in cardiac surgery patients. The overall goal is creating a dynamic resource of easily accessible educational material that will help to increase and improve compliance with the existing evidence-based best practices of patient blood management by cardiac surgery care teams.

Abstract Declining a donor when there is a reasonable possibility that the abnormality on chest imaging could be benign carries the risk of losing out on potentially usable lungs in an already parched landscape of donor organ availability. Cautiously aggressive attitudes to acceptance of borderline donors can help bridge the significant discrepancy that exists between the demand and availability of donor organs. Herein, we present a case highlighting successful bilateral lung transplantation from a relatively imperfect donor.

Abstract The MHC class I Ag presentation pathway in melanoma cells has a well-established role in immune-mediated destruction of tumors. However, the clinical significance of the MHC class II Ag presentation pathway in melanoma cells is less clear. In Ag-presenting cells, IFN-γ–inducible lysosomal thiol reductase (GILT) is critical for MHC class II–restricted presentation of multiple melanoma Ags. Although not expressed in benign melanocytes of nevi, GILT and MHC class II expression is induced in malignant melanocytes in a portion of melanoma specimens. Analysis of The Cancer Genome Atlas cutaneous melanoma data set showed that high GILT mRNA expression was associated with improved overall survival. Expression of IFN-γ, TNF-α, and IL-1β was positively associated with GILT expression in melanoma specimens. These cytokines were capable of inducing GILT expression in human melanoma cells in vitro. GILT protein expression in melanocytes was induced in halo nevi, which are nevi undergoing immune-mediated regression, and is consistent with the association of GILT expression with improved survival in melanoma. To explore potential mechanisms of GILT’s association with patient outcome, we investigated pathways related to GILT function and expression. In contrast to healthy skin specimens, in which the MHC class II pathway was nearly uniformly expressed and intact, there was substantial variation in the MHC class II pathway in the The Cancer Genome Atlas melanoma specimens. Both an active and intact MHC class II pathway were associated with improved overall survival in melanoma. These studies support a role for GILT and the MHC class II Ag presentation pathway in melanoma outcome.

Abstract We previously identified five single nucleotide polymorphisms (SNPs) at four susceptibility loci for diffuse large B-cell lymphoma (DLBCL) in individuals of European ancestry through a large genome-wide association study (GWAS). To further elucidate genetic susceptibility to DLBCL, we sought to validate two loci at 3q13.33 and 3p24.1 that were suggestive in the original GWAS with additional genotyping. In the meta-analysis (5662 cases and 9237 controls) of the four original GWAS discovery scans and three replication studies, the 3q13.33 locus (rs9831894; minor allele frequency [MAF] = 0.40) was associated with DLBCL risk [odds ratio (OR) = 0.83, P = 3.62 × 10−13]. rs9831894 is in linkage disequilibrium (LD) with additional variants that are part of a super-enhancer that physically interacts with promoters of CD86 and ILDR1. In the meta-analysis (5510 cases and 12 817 controls) of the four GWAS discovery scans and four replication studies, the 3p24.1 locus (rs6773363; MAF = 0.45) was also associated with DLBCL risk (OR = 1.20, P = 2.31 × 10−12). This SNP is 29 426-bp upstream of the nearest gene EOMES and in LD with additional SNPs that are part of a highly lineage-specific and tumor-acquired super-enhancer that shows long-range interaction with AZI2 promoter. These loci provide additional evidence for the role of immune function in the etiology of DLBCL, the most common lymphoma subtype.

This is a condensed summary of an international multisociety statement on ethics of artificial intelligence (AI) in radiology produced by the ACR, European Society of Radiology, RSNA, Society for Imaging Informatics in Medicine, European Society of Medical Imaging Informatics, Canadian Association of Radiologists, and American Association of Physicists in Medicine. AI has great potential to increase efficiency and accuracy throughout radiology, but it also carries inherent pitfalls and biases. Widespread use of AI-based intelligent and autonomous systems in radiology can increase the risk of systemic errors with high consequence and highlights complex ethical and societal issues. Currently, there is little experience using AI for patient care in diverse clinical settings. Extensive research is needed to understand how to best deploy AI in clinical practice. This statement highlights our consensus that ethical use of AI in radiology should promote well-being, minimize harm, and ensure that the benefits and harms are distributed among stakeholders in a just manner. We believe AI should respect human rights and freedoms, including dignity and privacy. It should be designed for maximum transparency and dependability. Ultimate responsibility and accountability for AI remains with its human designers and operators for the foreseeable future. The radiology community should start now to develop codes of ethics and practice for AI that promote any use that helps patients and the common good and should block use of radiology data and algorithms for financial gain without those two attributes.

Abstract Purpose: The surface receptor MET is highly expressed on primary uveal melanoma; MET inhibitors demonstrated early clinical signals of efficacy in slowing uveal melanoma growth. The primary objective of our study was to compare the progression-free survival rate at 4 months (PFS4) of patients with uveal melanoma treated with cabozantinib or chemotherapy. Patients and Methods: Patients with metastatic uveal melanoma and RECIST measurable disease were randomized 2:1 to receive either cabozantinib (arm 1) versus temozolomide or dacarbazine (arm 2) with restaging imaging every two cycles. Cross-over from arm 2 to cabozantinib after progression was allowed (arm 2X). Available tumor specimens were analyzed by whole-exome sequencing (WES) and results were correlated with outcome. Results: Forty-six eligible patients were accrued with 31, 15, and 9 in arms 1, 2, and 2X, respectively. Median lines of prior therapy, including hepatic embolization, were two. Rates of PFS4 in arm 1 and arm 2 were 32.3% and 26.7% (P = 0.35), respectively, with median PFS time of 60 and 59 days (P = 0.964; HR = 0.99). Median overall survival (OS) was 6.4 months and 7.3 months (P = 0.580; HR = 1.21), respectively. Grade 3–4 Common Terminology Criteria for Adverse Events were present in 61.3%, 46.7%, and 37.5% in arms 1, 2, and 2X, respectively. WES demonstrated a mean tumor mutational burden of 1.53 mutations/Mb and did not separate OS ≤ or &gt;1 year (P = 0.14). Known mutations were identified by WES and novel mutations were nominated. Conclusions: MET/VEGFR blockade with cabozantinib demonstrated no improvement in PFS but an increase in toxicity relative to temozolomide/dacarbazine in metastatic uveal melanoma.

Importance Preoperative assessment of nasal soft-tissue envelope (STE) thickness is an important component of rhinoplasty that presently lacks validated tools. Objective To measure and assess the distribution of nasal STE thickness in a large patient population and to determine if facial plastic surgery clinicians can predict nasal STE thickness based on visual examination of the nose. Design, Setting, and Participants This retrospective review and prospective assessment of 190 adult patients by 4 expert raters was conducted at an academic tertiary referral center. The patients had high-resolution maxillofacial computed tomography (CT) scans and standardized facial photographs on file and did not have a history of nasal fracture, septal perforation, rhinoplasty, or other surgery or medical conditions altering nasal form. Data were analyzed in March 2019. Main Outcomes and Measures Measure nasal STE thickness at defined anatomic subsites using high-resolution CT scans. Measure expert-predicted nasal STE thickness based on visual examination of the nose using a scale from 0 (thinnest) to 100 (thickest). Results Of the 190 patients, 78 were women and the mean (SD) age was 45 (17) years. The nasal STE was thickest at the sellion (mean [SD]) (6.7 [1.7] mm), thinnest at the rhinion (2.1 [0.7] mm), thickened over the supratip (4.8 [1.0] mm) and nasal tip (3.1 [0.6] mm), and thinned over the columella (2.6 [0.4] mm). In the study population, nasal STE thickness followed a nearly normal distribution for each measured subsite, with the majority of patients in a medium thickness range. Comparison of predicted and actual nasal STE thickness showed that experts could accurately predict nasal STE thickness, with the highest accuracy at the nasal tip ( r , 0.73; prediction accuracy, 91%). A strong positive correlation was noted among the experts’ STE estimates ( r , 0.83-0.89), suggesting a high level of agreement between individual raters. Conclusions and Relevance There is variable thickness of the nasal STE, which influences the external nasal contour and rhinoplasty outcomes. With visual analysis of the nose, experts can agree on and predict nasal STE thickness, with the highest accuracy at the nasal tip. These data can aid in preoperative planning for rhinoplasty, allowing implementation of preoperative, intraoperative, and postoperative strategies to optimize the nasal STE, which may ultimately improve patient outcomes and satisfaction. Level of Evidence NA .