Citations

Abstract Background and Aims The correlation between genotype and phenotype is well described in ADPKD adults. PKD2 is milder than PKD1 disease, with end stage kidney disease (ESKD) occurring on average 20 years later, and patients with PKD1 truncating mutations having a more severe outcome than PKD1 non-truncating mutations. Still, large differences in outcome occur even within families carrying the same gene variation. Only a few cases series reported the genetic profile of severely affected ADPKD children and suggest an additional effect of hypomorphic genes. We therefore aim to analyse the geno-phenotype profile in a well characterized pediatric ADPKD cohort. Method Clinical, familial, biological and imaging data were collected longitudinally in children diagnosed with ADPKD. Genotypic analysis was done using a custom Agilent SureSelect gene panel containing 136 ciliopathy-associated genes, including PKD1 and PKD2. Mutations and/or variants identified were individually evaluated for pathogenicity. Results 57 ADPKD children from 44 families were diagnosed at a mean (± SD) age of 4.1 (±4.8) years. ADPKD diagnosis was made in 32 children (56%) because of asymptomatic screening as requested by the family; 7 (12%) due to presenting symptoms (6 due to urinary tract infection and 1 due to post-traumatic macroscopic hematuria); 9 (16%) due to a coincidental finding of renal cysts on US performed for another reason and in 9 cases (16%) a prenatal diagnosis was performed. Twenty-nine children (51%) met the definition of very-early onset (VEO) disease. We identified pathogenic mutations in 100% of our patients, in which the prevalence of PKD1 truncating, PKD1 non-truncating, PKD2 and GANAB mutations was 75%, 19%, 4%, and 2%, respectively. Four cases (7%) were due to a de novo mutation. Interestingly, in 29 patients (51%) the germline mutation was the only identified mutation. However, in the rest of the subjects additional variants were identified in other ciliopathy-associated genes. In 12 cases (21%) the additional identified variants found in either the PKD, PMM2, HNF1B, DNAJC1, CEP290, NEK1, MKKS, NPHP4 or PKHD1 genes were scored to have a potential phenotypic effect, which will be evaluated by continued follow-up of this cohort. Conclusion We report the first large cohort of genotyped ADPKD children, including an extensive panel of ciliopathy genes next to the PKD genes. Interestingly, we found a high prevalence of additional and potentially modifying variants in this young population.

Aims The aim of this study was to compare the ability of tantalum, 3D porous titanium, antibiotic-loaded bone cement, and smooth titanium alloy to inhibit staphylococci in an in vitro environment, based on the evaluation of the zone of inhibition (ZOI). The hypothesis was that there would be no significant difference in the inhibition of methicillin-sensitive or methicillin-resistant Staphylococcus aureus (MSSA/MRSA) between the two groups. Methods A total of 30 beads made of three different materials (tantalum/3D porous titanium and smooth titanium alloy) were bathed for one hour in a solution of 1 g vancomycin in 20 ml of sterile water for injection (bath concentration: 50 mg/mL). Ten 1 cm3 cylinders of antibiotic-loaded cement were also created by mixing standard surgical cement with 1 g of vancomycin in standardized sterile moulds. The cylinders were then placed on agar plates inoculated with MSSA and MRSA. The ZOIs were measured each day and the cylinders were transferred onto a new inoculated plate. Results For MSSA and MRSA, no inhibitory effect was found in the control group, and antibiotic-loaded smooth titanium alloy beads showed a short inhibitory effect until day 2. For MSSA, both tantalum and 3D porous titanium beads showed significantly larger mean ZOIs than cement beads (all p < 0.01) each day until day 7 for tantalum and until day 3 for 3D porous titanium. After six days, antibiotic-loaded cement had significantly larger mean ZOIs than the 3D porous titanium (p = 0.027), but no significant difference was found with tantalum (p = 0.082). For MRSA, both tantalum and 3D porous titanium beads had significantly larger mean ZOIs than antibiotic-loaded cement each day until day 6 for tantalum (all p < 0.01) and until day 3 for 3D porous titanium (all p < 0.04). Antibiotic-loaded cement had significantly larger mean ZOIs than tantalum and 3D porous titanium from day 7 to 9 (all p < 0.042). Conclusion These results show that porous metal implants can deliver local antibiotics over slightly varying time frames based on in vitro analysis. Cite this article: Bone Joint J 2020;102-B(6 Supple A):158–162.

11012 Background: The proportion of women in the field of hematology and oncology (H&O) has increased over recent decades, but representation by women in leadership positions remains a challenge. Our aim was to examine representation of winners of recognition awards by gender and race from the major international hematology and oncology societies. Methods: Published award recipients from the seven major H&O societies were reviewed, with 26 years of data included (1994-2019). Awardee demographics and academic rank were collected and included in the analysis. Gender was determined based on awardee full name and verified by public data. Chi-square and Cochran-Armitage tests were used to analyze the data. Results: Over the past 26 years, 942 awards were presented at the 7 major H&O societies. We excluded 27 gender specific awards from the analysis. Of the 915 awardees included in analysis, award recipients were overwhelmingly men (77.9%) and non-Hispanic white (84.7%). Gender breakdown by society is described in table. ESMO and ASTRO represented the lowest distribution of women at 9.1% and 11.1%, respectively. Women awardees received 30.3% of the awards categorized as humanistic and education-related, while only receiving 16.0% of awards in the basic sciences category (p<0.01). The Cochran-Armitage test demonstrated an upward trend in the number of women awardees, from 10% between 1994-1998 to 25.6% between 2014-2019 (p=0.0004). Over the past five years, the average proportion of women medical oncologists was 35.6% per the AAMC. In this time period, women oncologists have received only 24.0% of all awards, suggesting the awardees included in the study period do not represent the proportion women in the field (p=0.00424). Black, Hispanic, and Asian awardees represented 3.7%, 3.3%, and 6.8% of the total awardees, respectively. Of the 64 Black and Hispanic awardees, 60.9% of the awards were for investigating healthcare disparities and only 4.6% were given for basic science research. Conclusions: During our study period, women physicians and investigators were less likely to receive recognition awards from the seven major H&O societies compared to men. We also observed a considerable low proportion of minority awardees in all oncology subspecialties. While the proportion of women awardees has increased over time, significant underrepresentation remains. [Table: see text]

9520 Background: Capmatinib (INC280) has shown promising efficacy in patients (pts) with MET exon 14 ( METex14)–mutated NSCLC who were pretreated (cohort 4) or treatment (tx)-naïve (cohort 5b) in the ongoing, multicohort, phase 2 GEOMETRY mono-1 study. We report the results for pts enrolled in the expansion cohort 6 with either high-level MET amplification (gene copy number [GCN] ≥10) or METex14 mutation (any MET GCN) whose disease progressed on 1 prior line of systemic therapy. Methods: Adult pts (≥18 years), ECOG PS 0–1 who had ALK and EGFR wt, stage IIIB/IV NSCLC (any histology) received capmatinib tablets 400 mg twice daily (with or without food). Key efficacy endpoints were overall response rate (ORR) and duration of response (DOR) by blinded independent review committee (BIRC) per RECIST v1.1. Other secondary endpoints included investigator-assessed ORR, DOR, disease control rate (DCR), progression-free survival (PFS; BIRC and investigator assessment) and safety. Results: As of Jan 6, 2020, 34 NSCLC pts with METex14 mutation (n = 31) or high-level MET amplification (n = 3) were included in this analysis. Tx was ongoing for 38.2% of pts. In METex14-mutated NSCLC pts, per BIRC assessment: ORR was 48.4%, median DOR was 6.93 months (mo, not yet mature, 95% CI: 4.17–NE) and median PFS was 8.11 mo (not yet mature, 95% CI: 4.17–9.86). Investigator-assessed responses were similar to BIRC assessment (Table). Only 3 pts with high-level MET amplification were included in this cohort due to challenges in enrollment. All 3 pts had stable disease per BIRC assessment and were on treatment for 48, 85 and 97 days. Most common AEs (≥25%, all grades, N = 34) were peripheral edema (64.7%), nausea (35.3%), fatigue (29.4%), back pain (26.5%) and vomiting (26.5%). Data for pts with brain metastasis will be presented at the ASCO 2020 meeting. Conclusions: Capmatinib was confirmed to be efficacious in 2nd line, METex14-mutated NSCLC pts. This is the first cohort where capmatinib has been administered without fasting restriction and data confirm the favorable safety profile. Clinical trial information: NCT02414139 . [Table: see text]

e20068 Background: FL grade 3B (FL3B) is an aggressive subtype of FL with a distinct morphologic, cytogenetic and immunohistochemical profile that is associated with higher mortality compared to other subtypes of FL. FL3B is a rare disease, and data regarding its prognostication beyond grading is lacking. Recent data suggests that spleen and extranodal (EN) involvement on PET/CT predict early clinical failure in FL grades 1-3A[1]. We aimed to determine the incidence of spleen and EN involvement on PET/CT in FL3B, and whether these can predict EFS. Methods: Patients with untreated FL3B diagnosed between 2003-2016, with available pre-treatment PET/CT, were identified using the Mayo Clinic Lymphoma Database and the University of Iowa/Mayo Clinic Lymphoma SPORE database. 27 patients were included in this analysis. All but two patients received treatment with immunochemotherapy. Associations with outcomes were assessed using EFS, defined as disease progression, relapse, transformation, or death. Results: 11/27 (40.7%) of patients had EN involvement on PET/CT. The most common EN site was bone, in 8/27 (29.5%) of patients. Soft tissue involvement was present in 4/27 (14.8%) of patients. Liver, brain, and endometrial involvement were each noted once. 11/27 (40.7%) of patients had spleen involvement on PET/CT. Presence of bone involvement as detected on PET/CT was associated with lower EFS (p = 0.02). EN involvement was associated with a trend toward a lower EFS but statistical significance was not reached likely secondary to low numbers in this cohort. Results in the table are compared to results obtained from our analysis in patients with FL grade 1-3A[1]. Conclusions: Bone involvement on pre-treatment PET/CT in FL3B was associated with early clinical failure in this small cohort of 27 patients. EN involvement at diagnosis may also be associated with poorer outcomes. These findings are similar to our analysis of a large (n = 613) cohort of patients with FL grade 1-3A. These findings may aid in the prognostication of patients with newly diagnosed FL3B, to guide therapy in select higher risk patients. [Table: see text]

8052 Background: A significant proportion of patients with FL experience an early relapse and a subsequent poor outcome. While several prognostic indices have been developed, none were designed to predict early failure. Recently, we established that lack of intrafollicular CD4+ T-cell expression predicted risk of early failure, and integrating this microenvironment biomarker with the Follicular Lymphoma International Prognostic Index, termed BioFLIPI, further improved identification of FL patients at risk of early failure ( Blood 2019;134(suppl1):121). However, the microenvironment may be influenced by the genetic composition of tumor. We investigated whether the CD4 biomarker and BioFLIPI were impacted by genetic features of the tumor as assessed by a 23-gene expression prognostic score ( Lancet Oncol 2018;19:549-61). Methods: Of the 186 cases with FL grade 1-3A treated with immunochemotherapy (IC) in our prior study, 152 had digital expression quantification of 23 selected genes (23-GEP score), which used RNA from formalin-fixed, paraffin-embedded samples. Event-free survival (EFS) was defined as time from diagnosis to progression, relapse, retreatment, or death. Early failure was defined as failing to achieve EFS at 24 months. Risk of early failure was estimated using odds ratios (ORs) and 95% confidence intervals from logistic regression models. We also used Cox regression to assess associations with continuous EFS and overall survival (OS). Results: 28% of patients failed to achieve EFS24. Lack of CD4+ intrafollicular expression (38% of patients, OR = 2.33, p = 0.024) and high risk 23-GEP score (26% of patients, OR = 3.52, p = 0.001) each predicted early failure, and in a multivariable model that included FLIPI, both CD4+ (OR = 2.26, p = 0.046) and 23-GEP score (OR = 2.26, p = 0.0.057) remained predictors. Similarly, BioFLIPI modeled as a continuous score (1-4, OR per one point increase = 2.31, p < 0.001) predicted early failure, and the association remained (OR = 2.14, p < 0.001) when the high risk 23-GEP score (OR = 2.79, p = 0.013) was included in the model. When stratified on 23-GEP score, BioFLIPI was a stronger predictor of early failure in low risk (74%, OR = 2.51, p = 0.002) relative to high risk (26%, OR = 1.55, p = 0.27) patients. Similar patterns were observed for EFS and OS. Conclusions: CD4+ T-cell infiltrate and tumor gene expression appear to be independently predictive of early failure in newly diagnosed FL patients treated with IC. Future studies should integrate and validate these measures.

Background Anatomic total shoulder arthroplasty improves pain and function with a reported reoperation rate of approximately 1% per year. With improved glenoid fixation, reverse shoulder arthroplasty implants may outperform anatomic total shoulder arthroplasty. We evaluate the functional outcomes and reoperation rate of anatomic total shoulder arthroplasty versus reverse shoulder arthroplasty at a minimum eight-year follow-up or revision. Methods Between 2005 and 2010, 187 shoulders (137 anatomic total shoulder arthroplasty, 50 reverse shoulder arthroplasty) were retrospectively reviewed at a mean of 8.8 years. The mean age at surgery was 67 years. Females were more commonly treated with reverse shoulder arthroplasty. Both groups had similar body mass index and comorbidities. Outcome measures evaluated included abduction, forward elevation, external rotation, internal rotation, Simple Shoulder Test, Constant score, American Shoulder and Elbow Score, University of California Los Angeles Shoulder score, and Shoulder Pain and Disability Index. Results At follow-up, anatomic total shoulder arthroplasty demonstrated greater overhead range of motion and external rotation. All patient-reported outcomes remained similar between groups. Reverse shoulder arthroplasty patients were more likely to rate shoulders as much better or better after surgery (90% versus 67%, p = 0.004). Complications were observed in 24% of anatomic total shoulder arthroplasties and 8% of reverse shoulder arthroplasties (p = 0.02). Reoperation was more common in anatomic total shoulder arthroplasties (23% versus 4%, p = 0.003). Discussion At mid-to-long-term follow-up, reverse shoulder arthroplasties demonstrated significantly fewer complications and reoperations than anatomic total shoulder arthroplasties. Despite similar patient-reported outcomes, reverse shoulder arthroplasty patients were more likely to be satisfied with their shoulder.

AbstractBackgroundStandard bone marrow biopsy (BMB) and bone involvement with follicular lymphoma (FL) on positron emission tomography (PET)/computed tomography (CT) both predict early clinical failure in FL. The key clinical question is whether PET/CT findings can obviate the need for BMB. The goal of this study was to determine the value of PET/CT in determining bone involvement in FL, using posterior iliac crest BMB as the gold standard.Materials and MethodsA total of 548 patients with newly diagnosed grade 1–3A FL were included. The presence, pattern, and location of bone involvement, spleen involvement, and standardized uptake values (SUVs) in the L3 vertebral body were recorded for all patients and compared with the BMB report.ResultsExcluding patients with focal bone lesions on PET/CT, the sensitivity and specificity of PET/CT in detecting bone or marrow involvement, compared with BMB, were 53% and 88%, respectively. The sensitivity and specificity of spleen involvement on PET/CT in predicting a positive BMB were 55% and 86%, respectively. An L3 SUVmax of less than 2.0 resulted in a negative predictive value (NPV) of 96% for marrow involvement on BMB; an L3 SUVmean below 1.4 resulted in an NPV of 100%.ConclusionIn newly diagnosed FL, PET/CT-detected bone and splenic involvement is highly specific for a positive BMB, and very low SUV values (&lt;2.0 SUVmax and &lt; 1.4 SUVmean) in the lumbar spine have a high NPV for a negative BMB. Routine BMB may be obviated in these patients. BMB remains necessary to definitively exclude bone marrow involvement in a large majority of patients with a negative PET.Implications for PracticePredicting early clinical failure in follicular lymphoma (FL) is important but difficult. Bone marrow involvement by FL is associated with early clinical failure, and determining this involvement is a key component of the initial staging. This study highlights that in certain patients, positron emission tomography/computed tomography is sufficient in determining bone or marrow involvement, without the need for a confirmatory bone marrow biopsy (BMB). An algorithm is provided based on these findings to help clinicians determine which patients would benefit from BMB and when it can be avoided.

Abstract The outcome of patients (pts) with WM, a rare B-cell malignancy, varies widely. The international community has convened a panel to develop a prognostically meaningful staging system for survival after treatment initiation. Toward establishing IPSS, we performed multivariate analyses with bootstrap validation in a series of 587 pts (median age 67, range: 28 to 95, M/F ratio: 1.7) diagnosed between September 1979 and December 2001. Diagnostic and treatment criteria fulfilled recommendations of the 2nd international WM workshop. Front-line treatment was initiated at diagnosis in 69% and 4 mo to 164 mo later in the remaining pts. Criteria for initiation of therapy included cytopenia, constitutional symptoms, organomegaly, hyperviscosity, IgM-related disorders, which pertained to 51%, 44%, 35%, 31% and 13%, respectively. Treatment regimens comprised alkylating agents, fludarabine and rituximab in 369, 195 and 23 subjects, respectively. Baseline parameters included age&gt;65 yr in 57%, Hb≤11.5 g/dL in 65%, platelet count ≤100 x109/L in 9%, granulocyte count ≤1.5 x109/L in 9%, B2M &gt;3 mg/L in 56%, albumin ≤3.5 g/dL in 36% and monoclonal protein &gt;7.0 g/dL in 7%. With a median follow-up of 64 mo (range, 6 mo–182 mo), the median survival after treatment initiation was 87 mo (95%CI 79–103) regardless of the type of therapy applied (p=0.3). Using results of univariate survival analyses, recursive partitioning and martingale residuals analyses, 7 adverse characteristics for inclusion in multivariate analyses were identified during an expert meeting: age &gt;65 yr, platelet count ≤ 100x109/L, B2M &gt;3 mg/L, M-protein &gt;7.0 g/dL, granulocytes ≤1.5 x109/L, Hb ≤11.5 g/dL and albumin ≤3.5 g/dL. The Cox proportional hazard model with stepwise selection selected the first 6 covariates. Bootstrap resampling (500 replicates) validated the selection of the first 4 covariates in at least 80% of the replicates. Selection of at least one of the last 2 covariates in more than 80% of the replicates indicated a correlation between these 2 covariates, and validated the inclusion of Hb only. Using the combination of age, Hb, platelet count, B2M and M-protein, low risk was defined by the presence of ≤1 adverse characteristic except age, high risk by the presence of &gt;2 adverse characteristics; the remaining patients with 2 adverse characteristics or age &gt;65yr had intermediate risk, comprising 27%, 38% and 35% of patients with 5-yr survival rates of 87%, 68% and 36% (p&lt;0.0001), independent of treatment and age. IPSS split each subgroup identified by previous scoring systems (Morel, Merlini, Dhodapkar). Conversely, log-rank test was significant only when the latter prognostic system was assessed in low IPSS-risk pts. Thus the combination of age, B2M, M-protein and blood counts provides simple prognostic model for survival in WM, hopefully serving as an objective basis for initiation of therapy and comparison of treatment results.