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Fungal and mycobacterial cultures should not be routinely obtained for diagnostic work-up of patients with suspected periprosthetic joint infections
Tai, Don Bambino Geno , Wengenack, Nancy L. , Patel, Robin , Berbari, Elie F. , Tande, Aaron J. , Tande, Aaron , Patel, Robin , Tai, Don Bambino Geno , Abdel, Matthew P.

The Bone & Joint Journal | December 31, 2021 | Volume: 104-B | Issue: 1 | Pages: 53-58

10.1302/0301-620x.104b1.bjj-2021-0876.r1 | PMID 34969277 Get It

Aims Fungal and mycobacterial periprosthetic joint infections (PJI) are rare events. Clinicians are wary of missing these diagnoses, often leading to the routine ordering of fungal and mycobacterial cultures on periprosthetic specimens. Our goal was to examine the utility of these cultures and explore a modern bacterial culture technique using bacterial blood culture bottles (BCBs) as an alternative. Methods We performed a retrospective review of patients diagnosed with hip or knee PJI between 1 January 2010 and 31 December 2019, at the Mayo Clinic in Rochester, Minnesota, USA. We included patients aged 18 years or older who had fungal, mycobacterial, or both cultures performed together with bacterial cultures. Cases with positive fungal or mycobacterial cultures were reviewed using the electronic medical record to classify the microbiological findings as representing true infection or not. Results There were 2,067 episodes of PJI diagnosed within the study period. A total of 3,629 fungal cultures and 2,923 mycobacterial cultures were performed, with at least one of these performed in 56% of episodes (n = 1,157). Test positivity rates of fungal and mycobacterial cultures were 5% (n = 179) and 1.2% (n = 34), respectively. After a comprehensive review, there were 40 true fungal and eight true mycobacterial PJIs. BCB were 90% sensitive in diagnosing true fungal PJI and 100% sensitive in detecting rapidly growing mycobacteria (RGM). Fungal stains were performed in 27 true fungal PJI but were only positive in four episodes (14.8% sensitivity). None of the mycobacterial stains was positive. Conclusion Routine fungal and mycobacterial stains and cultures should not be performed as they have little clinical utility in the diagnosis of PJI and are associated with significant costs. Candida species and RGM are readily recovered using BCB. More research is needed to predict rare non- Candida fungal and slowly growing mycobacterial PJI that warrant specialized cultures. Cite this article: Bone Joint J 2022;104-B(1):53–58.
Factors Affecting the Risk of Aseptic Patellar Complications in Primary TKA Performed with Cemented All-Polyethylene Patellar Resurfacing
Limberg, Afton K. , Tibbo, Meagan E. , Ollivier, Matthieu , Tammachote, Nattapol , Abdel, Matthew P. , Berry, Daniel J. , Abdel, Matthew P , Berry, Daniel J , Limberg, Afton K. , Tibbo, Meagan E. , Ollivier, Matthieu , Tammachote, Nattapol

Journal of Bone and Joint Surgery | December 21, 2021 | Volume: 104 | Issue: 5 | Pages: 451-458

10.2106/jbjs.21.00356 | PMID 34932523 Get It

Background: Patellar complications are a consequential cause of failure of primary total knee arthroplasty (TKA). The purpose of this study was to evaluate the association of demographic and patient factors with the long-term risk of patellar complications as a function of time in a very large cohort of primary TKAs performed with patellar resurfacing. Methods: We identified 27,192 primary TKAs utilizing cemented all-polyethylene patellar components that were performed at a single institution from 1977 through 2015. We evaluated the risk of any aseptic patellar complication and any aseptic patellar reoperation or revision, subanalyzed risks of reoperation or revision for loosening, maltracking/instability, and wear, and evaluated the risk of clinical diagnosis of patellar fracture and clunk/crepitus. The mean age at TKA was 68 years (range, 18 to 99 years); 57% of the patients were female. The mean body mass index (BMI) was 32 kg/m 2 . The primary diagnosis was osteoarthritis in 83%, and 70% of the TKAs were posterior-stabilized. Median follow-up was 7 years (range, 2 to 40 years). Risk factors for each outcome were evaluated with Cox regression models. Results: Nine hundred and seventy-seven knees with all-polyethylene patellae developed patellar complications. Survivorship free from any aseptic patellar complication was 93.3% at 20 years. Twenty-year survivorship free from any aseptic patellar reoperation was 97.3% and free from any aseptic patellar revision was 97.4%. Fifteen-year survivorship for the same end points for procedures performed from 2000 to 2015 was 95.7%, 99.2% and 99.3% respectively, representing substantial improvements compared with implants placed before 2000. Univariate analysis demonstrated that male sex (hazard ratio [HR], 1.4), an age of <65 years (HR, 1.3), and a BMI of ≥30 kg/m 2 (HR, 1.2) were associated with increased risk of patellar complications (all p ≤0.01). Posterior-stabilized designs were associated with fewer patellar reoperations and revisions overall (HR, 0.4 and 0.4; p < 0.001) but higher risk of patellar clunk/crepitus (HR, 14.1; p < 0.001). Conclusions: The 20-year survivorship free from any aseptic patellar complication in this series of cemented all-polyethylene patellae was 93%. Important risk factors for any aseptic patellar complication were male sex, an age of <65 years, a BMI of ≥30 kg/m 2 , and a patella implanted before 2000. Level of Evidence: Prognostic Level IV . See Instructions for Authors for a complete description of levels of evidence.
Transcriptomic analysis of Streptococcus agalactiae periprosthetic joint infection
Masters, Thao , Greenwood‐Quaintance, Kerryl E. , Johnson, Stephen , Pu, Meng , Patel, Robin , Cho, Hye-Kyung, Jeraldo, Patricio R , Patel, Robin , Cho, Hye-Kyung , Jeraldo, Patricio , Chia, Nicholas , Abdel, Matthew P.

MicrobiologyOpen | December 17, 2021 | Volume: 10 | Issue: 6 | Pages: No page available

10.1002/mbo3.1256 | PMID 34964296 Get It

AbstractAlthough Streptococcus agalactiae periprosthetic joint infection (PJI) is not as prevalent as staphylococcal PJI, invasive S. agalactiae infection is not uncommon. Here, RNA‐seq was used to perform transcriptomic analysis of S. agalactiae PJI using fluid derived from sonication of explanted arthroplasties of subjects with S. agalactiae PJI, with results compared to those of S. agalactiae strain NEM316 grown in vitro. A total of 227 genes with outlier expression were found (164 upregulated and 63 downregulated) between PJI sonicate fluid and in vitro conditions. Functional enrichment analysis showed genes involved in mobilome and inorganic ion transport and metabolism to be most enriched. Genes involved in nickel, copper, and zinc transport, were upregulated. Among known virulence factors, cyl operon genes, encoding β‐hemolysin/cytolysin, were consistently highly expressed in PJI versus in vitro. The data presented provide insight into S. agalactiae PJI pathogenesis and may be a resource for identification of novel PJI therapeutics or vaccines against invasive S. agalactiae infections.
Candidacy for Extracorporeal Life Support in Children After Hematopoietic Cell Transplantation: A Position Paper From the Pediatric Acute Lung Injury and Sepsis Investigators Network’s Hematopoietic Cell Transplant and Cancer Immunotherapy Subgroup
Zinter, Matt S. , McArthur, Jennifer , Duncan, Christine , Adams, Roberta H. , Kreml, Erin M., Dalton, Heidi , Abdel‐Azim, Hisham , Rowan, Courtney M. , Gertz, Shira J. , Mahadeo, Kris M. , Randolph, Adrienne G. , Rajapreyar, Prakadeshwari , Steiner, Marie E. , Lehmann, Leslie , Adams, Roberta, Randolph, Adrienne G , Gertz, Shira J

Pediatric Critical Care Medicine | December 8, 2021 | Volume: 23 | Issue: 3 | Pages: 205-213

10.1097/pcc.0000000000002865 | PMID 34878420 Get It

OBJECTIVES: The last decade has seen improved outcomes for children requiring extracorporeal life support as well as for children undergoing hematopoietic cell transplantation. Thus, given the historically poor survival of hematopoietic cell transplantation patients using extracorporeal life support, the Pediatric Acute Lung Injury and Sepsis Investigators’ hematopoietic cell transplantation and cancer immunotherapy subgroup aimed to characterize the utility of extracorporeal life support in facilitating recovery from critical cardiorespiratory illnesses in pediatric hematopoietic cell transplantation patients. DATA SOURCES: All available published data were identified using a set of PubMed search terms for pediatric extracorporeal life support and hematopoietic cell transplantation. STUDY SELECTION: All articles that provided original reports of pediatric hematopoietic cell transplantation patients who underwent extracorporeal life support were included. Sixty-four manuscripts met search criteria. Twenty-four were included as primary reports of pediatric hematopoietic cell transplantation patients who underwent extracorporeal life support (11 were single case reports, four single institution case series, two multi-institution case series, and seven registry reports from Extracorporeal Life Support Organization, Pediatric Heath Information System, and Virtual Pediatric Systems). DATA EXTRACTION: All 24 articles were reviewed by first and last authors and a spread sheet was constructed including sample size, potential biases, and conclusions. DATA SYNTHESIS: Discussions regarding incorporation of available evidence into our clinical practice were held at biannual meetings, as well as through email and virtual meetings. An expert consensus was determined through these discussions and confirmed through a modified Delphi process. CONCLUSIONS: Extracorporeal life support in hematopoietic cell transplantation patients is being used with increasing frequency and potentially improving survival. The Pediatric Acute Lung Injury and Sepsis Investigators hematopoietic cell transplantation-cancer immunotherapy subgroup has developed a framework to guide physicians in decision-making surrounding extracorporeal life support candidacy in pediatric hematopoietic cell transplantation patients. In addition to standard extracorporeal life support considerations, candidacy in the hematopoietic cell transplantation population should consider the following six factors in order of consensus agreement: 1) patient comorbidities; 2) underlying disease necessitating hematopoietic cell transplantation; 3) hematopoietic cell transplantation toxicities, 4) family and patient desires for goals of care; 5) hematopoietic cell transplantation preparatory regimen; and 6) graft characteristics. Although risk assessment may be individualized, data are currently insufficient to clearly delineate ideal candidacy. Therefore, we urge the onco-critical care community to collaborate and capture data to provide better evidence to guide physicians’ decision-making in the future.
111. Duration of Antibiotic Therapy after Debridement and Implant Retention in Patients with Periprosthetic Joint Infections
Berbari, Elie F. , Lahr, Brian D. , Tai, Don Bambino Geno , Abdel, Matthew P. , Tande, Aaron J.

Open Forum Infectious Diseases | December 5, 2021 | Volume: 8 | Issue: Supplement_1 | Pages: S68-S69

10.1093/ofid/ofab466.111 Get It

Abstract Background Debridement, antibiotics, and implant retention (DAIR) is appropriate for select acute postoperative and hematogenous periprosthetic joint infections (PJIs). However, the optimal duration of antimicrobial therapy in patients treated with DAIR has not been defined. Therefore, we aimed to identify the ideal duration of parenteral and oral antibiotics after DAIR. Methods We performed a retrospective study of patients &gt;18 years of age with hip or knee PJI managed with DAIR between January 1, 2008, and December 31, 2018, at Mayo Clinic. PJI was defined using criteria adapted from the International Consensus Meeting on PJI. The outcome was defined as either PJI recurrence or unplanned reoperation due to infection. Joint-stratified Cox proportional hazards regression models with time-dependent covariates were used to assess nonlinear effects of antibiotic duration. Hazard ratios were computed based on prespecified time points for comparison, whereas p-values represented the overall effect across the entire range of durations. Results There were 247 unique episodes of PJI in 237 patients during the study period. Parenteral antibiotics were given in 99.2% of cases (n=245). This was followed by chronic oral antibiotic suppression in 92.2% (n=226) with a median duration of 2.2 years (1.0-4.1). DAIR failed in 65 cases over a median follow-up of 4.4 years, with a 5-year cumulative incidence of 28.1%. After adjustment for risk factors, there was no significant association between duration of parenteral antibiotics and treatment failure (p=0.203), with no difference between four versus six weeks (HR 1.11; 95% CI 0.71-1.75) (Figure 1). However, both use and longer duration of oral antibiotic therapy was associated with a lower risk of failure (p=0.006). To account for the possibility that this association was driven by results during early follow-up, conditional analyses at one- and two-year follow-up were performed. Both showed a significantly lower risk for a longer duration of antibiotics (Figure 2). Figure 1. Time-Dependent Analysis of Parenteral Antibiotic Duration Figure 2. Time-Dependent Analysis of Oral Antibiotic Suppression Duration Conclusion After DAIR, efficacy from four weeks of parenteral antibiotics was no different from six weeks when followed by chronic oral antibiotic suppression. Our results could not establish an optimal duration but suggested that continuing suppression portends a lower risk of failure of DAIR. Disclosures Elie Berbari, MD, Uptodate.com (Other Financial or Material Support, Honorary unrelated to this work) Matthew P. Abdel, MD, Stryker and AAOS Board of Directors (Board Member, Other Financial or Material Support, Royalties) Aaron J. Tande, MD, UpToDate.com (Other Financial or Material Support, Honoraria for medical writing)
Transcriptomic analysis of Streptococcus agalactiae periprosthetic joint infection
Masters, Thao , Greenwood‐Quaintance, Kerryl E. , Johnson, Stephen , Pu, Meng , Cho, Hye-Kyung , Jeraldo, Patricio , Chia, Nicholas , Abdel, Matthew P. , Patel, Robin

No container title available | November 27, 2021 | Volume: No volume available | Issue: No issue available | Pages: No page available

10.22541/au.163803783.32306564/v1 Get It

Although Streptococcus agalactiae periprosthetic joint infection (PJI) is not as prevalent as staphylococcal PJI, invasive S. agalactiae infection has recently increased in incidence. Here, RNA-Seq was used to perform transcriptomic analysis of S. agalactiae PJI using fluid derived from sonication of explanted arthroplasties of subjects with S. agalactiae PJI, with results compared to those of S. agalactiae strain NEM316 grown in vitro. 227 genes with outlier expression were found (164 up-regulated and 63 down-regulated) between PJI sonicate fluid and in vitro conditions. Functional enrichment analysis showed genes involved in mobilome and inorganic ion transport and metabolism to be most enriched. Genes involved in nickel, copper, and zinc transport, were upregulated. Among known virulence factors, cyl operon genes, encoding beta-hemolysin/cytolysin, were consistently highly expressed in PJI versus in vitro. The data presented provide insight into S. agalactiae PJI pathogenesis and may be a useful resource for the identification of novel PJI therapeutics or vaccines against invasive S. agalactiae infections.
Unique Characteristics and Outcomes of Therapy-Related Acute Lymphoblastic Leukemia (trALL) Following Therapy for Multiple Myeloma (MM)
Wieczorek, Mikolaj A. , Jiang, Liuyan , Litzow, Mark R. , Sher, Taimur , Bergsagel, Leif, Kharfan‐Dabaja, Mohamed A. , Foran, James M. , Parrondo, Ricardo D , Rahman, Zaid Abdel , Heckman, Michael G. , Alkhateeb, Hassan B. , Greipp, Patricia T. , Bergsagel, P. Leif , Fonseca, Rafaël , Roy, Vivek , Dispenzieri, Angela , Murthy, Hemant S. , Ailawadhi, Sikander

Blood | November 24, 2021 | Volume: 138 | Issue: Supplement 1 | Pages: 2285-2285

10.1182/blood-2021-151574 Get It

Abstract Background: trALL is an important secondary primary malignancy (SPM) that has recently been appreciated. While patients (pts) with MM have an 8%-17% risk of developing an SPM while on lenalidomide (R) maintenance following autologous stem cell transplant (ASCT), trALL has been rarely observed. Little is known about the characteristics of trALL in pts with MM compared to pts who had other malignancies prior to the development of trALL. We define tALL as any prior exposure to cytotoxic chemotherapy and/or radiation for another malignancy, and herein, we report a comparative analysis of characteristics and outcomes of pts with trALL with and without MM from the Mayo Clinic Cancer Center (MCCC). Methods: We performed a systematic search in the 3-site MCCC registry and included all pts diagnosed and received at least 1 cycle of ALL-directed therapy and/or underwent allogeneic transplantation (AlloHCT) for ALL between 2007-2020. All cases of trALL in this series are B-ALL. Comparisons of characteristics between trALL patients with and without MM were made using a Wilcoxon rank sum test (continuous variables) or Fisher's exact test (categorical variables). Time-to-event variables were compared using unadjusted Cox proportional hazards regression models. Results: 70 trALL pts (14 MM [20%], 56 non-MM [80%]) were identified during the study period. The median age at trALL diagnosis was 63.9 (range 47-71) for MM pts and 63.1 (range 18.2-84) for non-MM pts. Median follow-up from trALL diagnosis was 1.42 years (range 0.02-10.6 years). The most common prior non-MM malignancies among tALL pts were breast (28.6%), lymphoma (17.9%), myeloid (17.9%), and GU/GYN (14.3%). Amongst the 14 MM pts, 100% (n=10) had ISS-I disease, 8 (57%) had IgG K MM, 1 (n=10) had high risk cytogenetics, 8 (57.1%) received R-based induction , 4 (28.6%) received CyBorD induction, 4(28.6%) received VRD induction, 3 (21.4%) received RD induction. 10 (71.4%) pts were actively on R when they developed trALL, 8 (57.1%) pts received prior ASCT. The median time to develop trALL following ASCT for MM was 46.3 months (m), (95% CI 20.4-67.6), 12 (85.7%) pts received R maintenance with a median duration of 53m (95% CI 16.9-121). The median time to develop trALL after initiation of R maintenance was 61.2m (95% CI 16.9-123.4). The most common trALL induction regimen received was HyperCVAD which was used in 71.4% of MM pts and 51.8% of non-MM pts. In comparison to non-MM pts, MM patients had a significantly lower WBC at diagnosis (Median: 2.0 vs. 5.8, P=0.005),no t(9;22) BCR/ABL1 cytogenetics (0.0% vs. 35.7%, P=0.008), a higher frequency of hypodiploid/near-triploid (Ho-Tri) cytogenetics (42.9% vs. 12.5%, P=0.009), and a lower frequency of prior radiation therapy (7.1% vs. 44.6%, P=0.012). MM pts had a higher frequency of AlloHCT for trALL (71.4% vs. 42.9%, P=0.075) and were more commonly in complete response (CR) at transplant (100.0% vs. 70.8%, P=0.078). No trALL in MM pts were Ph-like ALL. There was a statistically significant difference in time to development of trALL between previous malignancy locations (P=0.018), with GU/GYN (Median: 9 years) having the longest time and myeloid (Median: 3 years) having the shortest time; MM was 6 years. In the overall pt cohort, 56 (80%) pts achieved a complete response after induction and 60% (n=25) were minimal residual disease (MRD)+ after induction. Pts with MM had a significantly lower likelihood of being MRD+ after induction (OR=0.09, P=0.015). Overall, 24.3% of pts relapsed after induction therapy for trALL; 39 (55.5%) died after trALL diagnosis including 43% (n=35) who died after AlloHCT. Although pts with MM tended to have better outcomes compared to non-MM trALL pts in terms of overall survival after trALL diagnosis (Figure 1A), survival after AlloHCT (Figure 1B), relapse rate after trALL diagnosis and non-relapse mortality after AlloHCT, none of these findings were statistically significant in this small cohort (Figure 1C). Conclusion: trALL is a unique SPM that can occur in pts with MM. It is associated with Ho-Tri cytogenetics and is BCR/ABL1 negative. The majority of MM pts that developed trALL had undergone prior ASCT and were on R maintenance when they developed trALL. Despite being more likely to have adverse cytogenetics features, MM-associated trALL has similar survival compared to non-MM-associated trALL which speaks to the poor survival outcomes of this SPM. Further research on trALL in MM pts is merited. Figure 1 Figure 1. Disclosures Litzow: Amgen: Research Funding; Pluristem: Research Funding; AbbVie: Research Funding; Actinium: Research Funding; Astellas: Research Funding; Omeros: Other: Advisory Board; Jazz: Other: Advisory Board; Biosight: Other: Data monitoring committee. Bergsagel: Janssen: Consultancy. Fonseca: Scientific Advisory Board: Adaptive Biotechnologies: Membership on an entity's Board of Directors or advisory committees; Caris Life Sciences: Membership on an entity's Board of Directors or advisory committees; AbbVie: Consultancy; Patent: Prognosticaton of myeloma via FISH: Patents & Royalties; Bayer: Consultancy; Takeda: Consultancy; Celgene: Consultancy; Amgen: Consultancy; BMS: Consultancy; Mayo Clinic in Arizona: Current Employment; Juno: Consultancy; Kite: Consultancy; Aduro: Consultancy; OncoTracker: Consultancy, Membership on an entity's Board of Directors or advisory committees; GSK: Consultancy; Novartis: Consultancy; Merck: Consultancy; Sanofi: Consultancy; Pharmacyclics: Consultancy; Janssen: Consultancy. Dispenzieri: Takeda: Research Funding; Alnylam: Research Funding; Pfizer: Research Funding; Oncopeptides: Consultancy; Sorrento Therapeutics: Consultancy; Janssen: Consultancy, Research Funding. Murthy: CRISPR Therapeutics: Research Funding. Ailawadhi: GSK: Consultancy, Research Funding; Sanofi: Consultancy; Pharmacyclics: Consultancy, Research Funding; Takeda: Consultancy; Medimmune: Research Funding; Xencor: Research Funding; Genentech: Consultancy; Janssen: Consultancy, Research Funding; Amgen: Consultancy, Research Funding; Cellectar: Research Funding; Beigene: Consultancy; BMS: Consultancy, Research Funding; AbbVie: Consultancy; Karyopharm: Consultancy; Ascentage: Research Funding. Foran: actinium: Research Funding; taiho: Honoraria; bms: Honoraria; servier: Honoraria; pfizer: Honoraria; novartis: Honoraria; OncLive: Honoraria; abbvie: Research Funding; boehringer ingelheim: Research Funding; takeda: Research Funding; trillium: Research Funding; aptose: Research Funding; revolution medicine: Honoraria; syros: Honoraria; sanofi aventis: Honoraria; certara: Honoraria; gamida: Honoraria; kura: Research Funding; h3bioscience: Research Funding; aprea: Research Funding; sellas: Research Funding; stemline: Research Funding.
Epidemiologic and Clinical Analysis of Tumor Mutational Burden (TMB) in Acute Myeloid Leukemia (AML): Exome Sequencing Study of the Mayo Clinic AML Epidemiology Cohort (MCAEC)
Foran, James M. , Cherukuri, Yesesri , Wieczorek, Mikolaj A. , Jiang, Liuyan , Finn, Laura , Sproat, Lisa Z., Lou, Yanyan , Asmann, Yan W. , Heckman, Michael G. , Rahman, Zaid Abdel , Murthy, Hemant S. , Badar, Talha , Cerhan, James R.

Blood | November 23, 2021 | Volume: 138 | Issue: Supplement 1 | Pages: 3437-3437

10.1182/blood-2021-151233 Get It

Abstract TMB is used to guide PD-1-directed immunotherapy in solid tumor Oncology. However, it has not been systematically studied in AML, where the focus has been on cytogenetic risk and individual driver gene mutations (GM's). TMB contribution to AML epidemiology is also uncertain. We therefore studied its association with epidemiologic risk factors; driver GM's and somatic mutations (SM's) in AML risk genes which we recently demonstrated (ABCB1; CYP1A1; CYP2B6; EPHX1; ERCC1,2,& 5; MEFV; MTRR; and TERT); clinical and cytogenetic features; and outcome after therapy in the MCAEC, a highly annotated clinical epidemiology cohort of consecutive AML pts [Finn, Cancer Epidemiol 39:1084, 2015]. Methods: We obtained somatic leukemia DNA from remnant diagnostic cytogenetic pellets in 98 MCAEC patients (pts), as previously described [Foran, Blood (2017) 130:570a]. Whole exome sequencing (WES) was performed at depth of ~100 million paired end 100bp reads using Agilent SureSelectXT Human All Exon V5 + UTRs target enrichment kit. Reads were mapped to human genome build hg19 using BWA-MEM. Single nucleotide variants (SNVs) and small INDELs were identified using Mayo Clinic (MC) analytic pipeline GenomeGPS 4.0.1 following Broad GATK variant discovery best practices of alignment, realignment and recalibration, and multi-sample joint genotyping; and filtered using both germline whole exome and genome sequencing of ~1200 MC Biobank samples and public germline variant databases of 1000 genome project, 6500 individuals in exome sequencing project, and HapMap phase 3. Remaining variants were annotated using ANNOVAR, and functional variants of non-synonymous, truncating, frame-shift, and splice-sites were used in the statistical association analyses. TMB was defined as the number of functional mutations per Mb of coding region, heterozygous or homozygous. TMB associations with epidemiologic risk, clinical characteristics, and SM's in AML risk genes (listed above) or driver GM's (occurring in 5 or more pts: ASXL1, BCOR, CEBPA, DNMT3A, FLT3, IDH2, KRAS, MLL2-5, NF1, NPM1, NRAS, PHF6, RUNX1, SF3B1, STAG2, TET2, TP53, U2AF1) were evaluated using linear regression models; a rank transformation of TMB was utilized due to its skewed distribution. Multivariable analysis (MVA) models were adjusted for variables with p-value &lt;0.05 in unadjusted analysis. Regression coefficients ("β") were estimated, interpreted as change in mean TMB rank for specified variables or characteristic. Associations with outcomes were examined using logistic regression or Cox proportional hazards regression models. All statistical tests were two-sided (version 3.6.2; R Foundation for Statistical Computing, Vienna, Austria). Results Median age at AML diagnosis was 70 yrs (Range: 19-94 yrs), and 67 pts were male. Cytogenetic risk group was favorable (7%), intermediate-normal (46%) or abnormal (20%), and poor risk (27%). 40/61 pts (66%) achieved complete remission (CR). With a median follow-up of 8.0 months (Range: 0.1 - 186), 80 pts (82%) died and 20 (20%) underwent allogeneic transplantation (AlloBMT). Median TMB was 18.2 (Range: 15.0-70.1). In MVA, significant associations with increased TMB were observed in pts with history of prior immunosuppressive therapy or solid organ transplantation (β=19.48, P=0.015), and with FLT3 (β=21.12, P=0.015), MLL2 (β=20.91, P=0.001), and MLL3 (β=11.31, P=0.031) GM's. A borderline association was observed for U2AF1 (β=16.14, P=0.057). TMB was also associated with SM's in TERT (β=25.13, P=0.028); a borderline association with SM's in ABCB1 was not confirmed in MVA (β=-17.98, P=0.069). Additionally, cytogenetic risk group was associated with TMB in MVA (P=0.005), being highest in intermediate-normal and lowest in poor risk groups. Body Mass Index was inversely associated with TMB (unadjusted β=-16.99, P=0.005), but unconfirmed in MVA (β=-8.29, P=0.12). There was no association with CR (OR=0.93, P=0.46), use of (HR=0.96, P=0.64) or relapse risk (HR=1.00, P=0.98) following AlloBMT, or survival (HR=0.97, P=0.56) (Figure). Conclusions Measurement of TMB is feasible in this AML epidemiologic cohort, and we observed important associations with AML risk factors, risk gene SM's, cytogenetic risk group, and driver GM's. We acknowledge the relatively small sample size and possibility of type II error, and therefore these observations require validation in a large prospective cohort which is planned. Figure 1 Figure 1. Disclosures Foran: OncLive: Honoraria; certara: Honoraria; actinium: Research Funding; boehringer ingelheim: Research Funding; novartis: Honoraria; abbvie: Research Funding; servier: Honoraria; taiho: Honoraria; pfizer: Honoraria; revolution medicine: Honoraria; gamida: Honoraria; takeda: Research Funding; sanofi aventis: Honoraria; trillium: Research Funding; syros: Honoraria; aptose: Research Funding; bms: Honoraria; kura: Research Funding; h3bioscience: Research Funding; aprea: Research Funding; sellas: Research Funding; stemline: Research Funding. Murthy: CRISPR Therapeutics: Research Funding. Finn: Jazz: Consultancy, Speakers Bureau; BMS: Consultancy, Speakers Bureau; BeiGene: Consultancy, Speakers Bureau; ADC Therapeutics: Consultancy, Speakers Bureau. Badar: Pfizer Hematology-Oncology: Membership on an entity's Board of Directors or advisory committees. Cerhan: Celgene/BMS: Other: Connect Lymphoma Scientific Steering Committee, Research Funding; Genentech: Research Funding; NanoString: Research Funding; Regeneron Genetics Center: Other: Research Collaboration.
CTNI-28. VOLUMETRIC AND DOSIMETRIC PATTERNS OF FAILURE ANALYSIS OF A PHASE II CLINICAL TRIAL OF 18F-DOPA-PET DIRECTED DOSE ESCALATED RADIOTHERAPY FOR GLIOBLASTOMA
Breen, William G. , Anderson, S. Keith , Pafundi, Deanna, Lowe, Val J. , Vogen, Diane, Yan, Elizabeth , Brown, Paul D. , Uhm, Joon H. , Ruff, Michael W. , Zakhary, Mark J. , Zhang, Yan , Seaberg, Maasa , Rehim, Abdou Abdel , Tseung, Hok Seum Wan Chan, Kabat, Brian, Kemp, Bradley J. , Brinkmann, Debra H. , Kaufmann, Timothy J. , Hunt, Christopher H. , Sarkaria, Jann N. , Kizilbash, Sani H. , Qian, Jing, Laack, Nadia N.

Neuro-Oncology | November 18, 2021 | Volume: 23 | Issue: Supplement_6 | Pages: vi65-vi65

10.1093/neuonc/noab196.253 Get It

Abstract While dose escalation of radiotherapy (DERT) has failed to improve overall survival (OS) or progression-free survival (PFS) for glioblastoma in previous studies, a recent phase II clinical trial utilizing 18F-DOPA-PET-directed DERT demonstrated improved PFS in MGMT-unmethylated patients and OS in MGMT-methylated patients compared to historical controls. This planned secondary analysis sought to determine 1) how 18F-DOPA-PET changes RT volumes beyond standard MRI-planning, 2) which patients benefit most and least from this protocol, 3) which are mostly likely to experience clinically significant radionecrosis after DERT, and 4) patterns of failure after DERT. For 69 evaluable patients, median MRI-defined, PET-defined, and combined low-dose gross tumor volumes (GTV51) were 54 cc (range 9-248), 23 cc (0.4-179), and 62 cc (10-260), respectively. Median MRI-defined, PET-defined, and combined high-dose GTVs (GTV76) were 32 cc (range 4-136), 6 cc (0.1-138), and 34 cc (4-162), respectively. 18F-DOPA-PET resulted in a median volumetric expansion of 13% (0-243%) and 5% (0-217%) from MRI-defined low-dose and high-dose GTV’s, respectively. Central failures ( &gt;95% of recurrence tumor volume) occurred within the 76 Gy, 60 Gy, and 51 Gy isodose lines in 32 (46%), 60 (87%), and 64 (93%) patients, respectively. Recursive partitioning analysis stratified patients by OS and PFS. Patients with 18F-DOPA-PET-defined GTV76 &gt; 7.8cc, MRI-defined GTV76 &gt; 42.7cc, and MGMT promotor-unmethylated tumors had the shortest OS, while patients with smaller PET and MRI-defined tumors had the longest OS (median 10.4 vs. 64.6 months, p&lt; 0.001). Similarly, PFS was worst in patients with 18F-DOPA-PET-defined GTV76 &gt; 2.17 cc who had biopsy only (median PFS 3.2 months, p&lt; 0.001). Patients with 18F-DOPA-PET-defined GTV51 &gt; 50 cc had the highest risk of grade 3+ radionecrosis (p&lt; 0.001). In conclusion, larger 18F-DOPA-PET and MRI-defined tumor volumes were associated with worse outcomes, and 18F-DOPA-PET-directed DERT appears to reduce risk of central recurrence in high-dose volumes.
Varus-valgus constrained insert with posterior-stabilized femoral components in complex primary total knee arthroplasties
Limberg, Afton K. , Hanssen, Arlen D. , Pagnano, Mark W. , Wyles, Cody C. , Taunton, Michael J. , Abdel, Matthew P.

Bone & Joint Open | November 9, 2021 | Volume: 2 | Issue: 11 | Pages: 921-925

10.1302/2633-1462.211.bjo-2021-0134.r1 | PMID 34751585 Get It

Aims Varus-valgus constrained (VVC) devices are typically used in revision settings, often with stems to mitigate the risk of aseptic loosening. However, in at least one system, the VVC insert is compatible with the primary posterior-stabilized (PS) femoral component, which may be an option in complex primary situations. We sought to determine the implant survivorship, radiological and clinical outcomes, and complications when this VVC insert was coupled with a PS femur without stems in complex primary total knee arthroplasties (TKAs). Methods Through our institution’s total joint registry, we identified 113 primary TKAs (103 patients) performed between 2007 and 2017 in which a VVC insert was coupled with a standard cemented PS femur without stems. Mean age was 68 years (SD 10), mean BMI was 32 kg/m2 (SD 7), and 59 patients (50%) were male. Mean follow-up was four years (2 to 10). Results The five-year survivorship free from aseptic loosening was 100%. The five-year survivorship free from any revision was 99%, with the only revision performed for infection. The five-year survivorship free from reoperation was 93%. The most common reoperation was treatment for infection (n = 4; 4%), followed by manipulation under anaesthesia (MUA; n = 2; 2%). Survivorship free from any complication at five years was 90%, with superficial wound infection as the most frequent (n = 4; 4%). At most recent follow-up, two TKAs had non-progressive radiolucent lines about both the tibial and femoral components. Knee Society Scores improved from 53 preoperatively to 88 at latest follow-up (p < 0.001). Conclusion For complex primary TKA in occasional situations, coupling a VVC insert with a standard PS femur without stems proved reliable and durable at five years. Longer-term follow-up is required before recommending this technique more broadly. Cite this article: Bone Jt Open 2021;2(11):921–925.