Citations

6016 Background: The role of HIPEC for recurrent EOC is not well defined. The aim of this phase II study was to determine the proportion of pts without evidence of disease progression at 24 months post SCS +/- intraoperative carboplatin HIPEC. Methods: After SCS to ≤ 0.5 cm residual visible disease pts were intraoperatively randomized to carboplatin HIPEC (800mg/m2 for 90 minutes) or no HIPEC. The HIPEC arm received 5 additional and the standard arm received 6 postoperative cycles of IV platinum-based chemotherapy without maintenance treatment. Based on an exact binomial single stage “pick the winner” design, each arm is considered “winner” if ≥ 17/49 pts are without evidence of disease progression at 24 months post SCS. Secondary objectives include postoperative grade ≥ 3 toxicity and complications within 4 weeks post SCS, and pharmacokinetics of carboplatin HIPEC. Results: Of 98 pts, 49 (50%) were randomized to the HIPEC arm. The arms were well balanced for age, stage, histology, BRCA mutation status, prior chemotherapy, and disease-free interval. Complete gross SCS was achieved in 94% of the standard and 82% of the HIPEC arm (p = 0.12). Bowel resection was performed more frequently in the standard (65%) compared to the HIPEC arm (37%; p = 0.008). Median operative time was shorter in the standard (296 minutes) compared to the HIPEC arm (475 minutes; p < 0.001). There was no perioperative mortality and no difference in use of ostomies, length of stay or postoperative toxicity. At a median follow-up of 27.7 months (range: 8.8-81.8 months) 70 of 98 pts progressed and 26 died with a median progression free survival (PFS) of 14.3 months (12.1-16 months) and a median overall survival (OS) of 55.2 months (47.7-not reached). At 24 months post SCS 32 pts progressed within 24 months in the standard versus 35 in the HIPEC arm. There was no statistically significant difference in median PFS (15.4 vs 12.3 months, p = 0.173) or median OS (69.2 vs 53.1 months, p = 0.317) between arms. These are preliminary efficacy estimates as 83/98 pts have a minimum of 24 months follow-up. Conclusions: The HIPEC arm did not reach the predefined “winner” endpoint; the standard arm is still undetermined as 6 pts did not reach 24 months follow-up. No perioperative mortality, and no increased perioperative morbidity or toxicity was seen with HIPEC. SCS with carboplatin HIPEC followed by 5 cycles of platinum-based chemotherapy was not superior to SCS without HIPEC followed by 6 cycles of platinum-based chemotherapy. Clinical trial information: NCT01767675.

2524 Background: Postoperative radiosurgery (SRS) has been associated with up to 30% risk of subsequent leptomeningeal disease (LMD). We previously demonstrated that radiographic pattern of LMD (classical “sugarcoating” [cLMD] vs. nodular [nLMD]) in this setting is prognostic. The association between radiographic pattern of LMD, type of salvage treatment (tx), and neurologic death (ND) has not been well described. Methods: The records of patients (pts) with brain metastases (BM), of which 1 was resected and treated with adjunctive SRS, and who subsequently developed LMD were combined from 7 tertiary care centers. Pts with classically radiosensitive tumors or prior or planned whole brain radiotherapy (WBRT) were excluded. ND was defined as symptomatic CNS progression around the time of death without life threatening systemic symptoms or progression. Salvage radiotherapy (RT) for LMD was categorized according to use of WBRT vs. focal cranial RT. Results: The study cohort consisted of 147 pts, of which 125 had died with known cause, 107 also received LMD salvage tx, and 82 also had cranial MRI follow-up. The ND rate in the 125 pts who died with known cause was 79%; the rate in pts who underwent LMD salvage tx (n = 107) was 76%. Univariate logistic regression demonstrated radiographic pattern of LMD (cLMD vs. nLMD, odds ratio [OR] 2.9, p = 0.04) and 2nd LMD failure after salvage tx (OR 3.9, p = 0.02) as significantly associated with ND. The ND rate was 86% for cLMD vs. 68% for nLMD pattern. WBRT was used in 95% of pts with cLMD vs. 52% of pts with nLMD. In the nLMD cohort (n = 58), there was no difference in ND rate based on type of salvage RT (WBRT: 67% vs. focal cranial RT: 68%, p = 0.92). Second LMD failure (vs. not) was associated with higher ND in the nLMD cohort (77% vs. 52%, p = 0.02). Of the 26 pts with nLMD who experienced 2nd LMD failure, 7 had classical 2nd LMD, of which 100% experienced ND, and 19 had nodular 2nd LMD, of which 68% experienced ND (p = 0.09). Conclusions: LMD after surgery and SRS for brain metastases is a clinically significant event with high rates of neurologic death. Classical LMD pattern (vs. nodular) and 2nd LMD failure after salvage tx were significantly associated with higher risk of neurologic death. In the nodular LMD cohort, radiographic pattern of 2nd LMD may be associated with risk of subsequent neurologic death. Pts with nodular LMD treated with salvage focal cranial RT or WBRT had similar risk of neurologic death. Methods to decrease LMD and the subsequent high risk of neurologic death in this setting warrant investigation.

Background: Meniscal root tears and ramp lesions have been rigorously characterized in recent literature. However, one of the most common lateral meniscal injuries identified with an acute anterior cruciate ligament (ACL) disruption, a posterior horn lateral meniscal oblique radial tear (LMORT), has not been thoroughly described. Purpose: To determine the incidence of all meniscal tears and, more specifically, the incidence of posterior horn LMORTs in a multicenter cohort of consecutive, acute ACL reconstructions. Additionally, the authors aimed to develop a new classification system to help guide treatment of posterior horn LMORTs. Study Design: Cross-sectional study; Level of evidence, 3. Methods: A multicenter retrospective cohort design was used to analyze 200 consecutive cases of acute ACL reconstruction from each of 3 different surgeons, for a total of 600 patients. The operative notes and intraoperative photos were analyzed to determine the incidence and laterality of all meniscal tears. A classification system based on tear characterization was then used to categorize tear patterns into similar groups. Results: A total of 396 (66%) of the 600 patients with acute ACL disruption had concomitant meniscal tears. Specifically, 187 (31%) had a lateral meniscal injury, 89 (15%) had a medial meniscal injury, and 122 (20%) had both medial and lateral meniscal injuries. The most common lateral meniscal tear was an LMORT; 71 (18%) patients with meniscal tears had a posterior horn LMORT. Overall, the incidence of ACL injury with a concomitant posterior horn LMORT was 12%. A classification was developed, which included type 1 tear (partial thickness <10 mm from the root attachment), type 2 tear (complete radial oblique tear that extended <10 mm from root), type 3 tear (incomplete LMORT that extended >10 mm from root), and type 4 tear (complete LMORT >10 mm from root). Conclusion: In 600 consecutive acute ACL reconstructions, the incidence of concomitant ACL injury with meniscal injury was 66%, and posterior horn LMORTs represented a large proportion of all meniscal tears (12%). A classification scheme was developed for posterior horn LMORTs to aid reporting and clinical decision making for these common tears.

Abstract Aims More evidence is needed to quantify the association between tricuspid regurgitation (TR) and mortality in patients with heart failure (HF). Methods and results Between 2008–2017, using the Optum longitudinal database, a patient-level database that integrates multiple US-based electronic health and claim records from several health care providers, we identified 435 679 patients with new HF diagnosis and both an assessment of the left ventricular ejection fraction and at least 1 year of history. TR was graded as mild, moderate or severe and classified as prevalent (at the time of the initial HF diagnosis) or incident (subsequent new cases thereafter). For prevalent TR, the analysis was performed using a Cox proportional hazards model with adjustment for patient covariates. Incident TR was modelled as a time-updated covariate, as were other non-fatal events during follow-up. Prevalence of mild, moderate and severe TR at baseline was 10.1%, 5.1% and 1.4%, respectively. Over a median follow-up of 1.5 years, 121 273 patients (27.8%) died and prevalent TR was independently associated with survival. Compared to patients with no TR at baseline, the adjusted hazard ratios for mortality were 0.99 [95% confidence interval (CI) 0.97–1.01], 1.17 (95% CI 1.14–1.20) and 1.34 (95% CI 1.28–1.39) for mild, moderate and severe TR, respectively. In the 363 270 patients free from TR at baseline, incident TR (at least mild, at least moderate, or severe) developed during follow-up in 12.1%, 5.1% and 1.1%, respectively. Adjusted mortality hazard ratios for such new cases were 1.48 (95% CI 1.44–1.52), 1.92 (95% CI 1.86–1.99) and 2.44 (95% CI 2.32–2.57), respectively. Findings were consistent across all patient subgroups based on age, gender, rhythm, associated comorbidities, prior cardiac surgery, B-type natriuretic peptide/N-terminal pro-B-type natriuretic peptide, and left ventricular ejection fraction. Conclusions In this large contemporary patient-level database of almost half-million US patients with HF, TR was associated with a marked increases in mortality risk overall and in all subgroups. Future randomized controlled trials will evaluate the impact of TR correction on clinical outcomes and the causal relationship between TR and mortality.

Abstract Background Multiple system atrophy (MSA) is a neurodegenerative disorder from α‐synuclein aggregation. in vitro studies suggest vitamin B12 may interrupt α‐synuclein‐mediated neurodegeneration. The objective of this study was to determine whether serum vitamin B12 level at MSA diagnosis is associated with survival. Methods One hundred eighty‐two MSA patients evaluated at Mayo Clinic with vitamin B12 testing were studied. We determined the risk of death in relationship to serum vitamin B12 levels at MSA diagnosis, adjusting for predictors of poor survival. Results Predictors of shorter survival included vitamin B12 < 367 ng/L (HR, 1.8; 95% CI, 1.3–2.7), falls within 3 years of MSA diagnosis (HR, 1.6; 95% CI, 1.1–2.3), bladder symptoms (HR, 1.6; 95% CI, 1.0–2.6), urinary catheter requirement (HR, 1.7; 95% CI, 1.0–2.8), male sex (HR, 1.4; 95% CI, 1.0–2.0), and MSA‐P subtype (HR, 1.5; 95% CI, 1.0–2.0). Conclusions Low vitamin B12 levels are associated with shorter survival in MSA. Additional studies to explore this observation and assess the potential role of vitamin B12 as a modifiable survival factor are needed. © 2020 International Parkinson and Movement Disorder Society

The American Society of Nephrology has established a new initiative, AKI!Now , with the goal of promoting excellence in the prevention and treatment of AKI by building a foundational program that transforms education and delivery of AKI care, aiming to reduce morbidity and associated mortality and to improve long-term outcomes. In this article, we describe our current efforts to improve early recognition and management involving inclusive interdisciplinary collaboration between providers, patients, and their families; discuss the ongoing need to change some of our current AKI paradigms and diagnostic methods; and provide specific recommendations to improve AKI recognition and care. In the hospital and the community, AKI is a common and increasingly frequent condition that generates risks of adverse events and high costs. Unfortunately, patients with AKI may frequently have received less than optimal quality of care. New classifications have facilitated understanding of AKI incidence and its impact on outcomes, but they are not always well aligned with AKI pathophysiology. Despite ongoing research efforts, treatments to promote or hasten kidney recovery remain ineffective. To avoid progression, the current approach to AKI emphasizes the promotion of early recognition and timely response. However, a lack of awareness of the importance of early recognition and treatment among health care team members and the heterogeneity of approaches within the health care teams assessing the patient remains a major challenge. Early identification is further complicated by differences in settings where AKI occurs (the community or the hospital), and by differences in patient populations and cultures between the intensive care unit and ward environments. To address these obstacles, we discuss the need to improve education at all levels of care and to generate specific guidance on AKI evaluation and management, including the development of a widely applicable education and an AKI management toolkit, engaging hospital administrators to incorporate AKI as a quality initiative, and raising awareness of AKI as a complication of other disease processes.

Abstract Introduction: Recent reviews indicate that transfusional hemosiderosis may be associated with an increased risk of mortality in lower-risk pts with MDS. This trial is designed to evaluate the efficacy and long-term safety of deferasirox (Exjade®, ICL670) in MDS. Deferasirox is an oral iron chelator approved for use in pts with transfusional iron overload. Methods: This is a Phase II, open-label, 3-yr clinical trial in 55 US centers, enrolling 150 pts (aged ≥18 years) with Low- or Int-1-risk MDS (by IPSS criteria) and transfusional iron overload (serum ferritin ≥1000 ng/mL and &gt;20 units RBC transfusions). Deferasirox dosing is 20–30 mg/kg/day. Serum ferritin, iron, transferrin and transferrin saturation are being assessed at screening and monthly in yr 1, then quarterly in yrs 2 and 3, while labile plasma iron (LPI) is assessed quarterly in yr 1. In addition, creatinine, calculated creatinine clearance, echocardiograms and endocrine and hematological status are being assessed. This report describes baseline data in these pts. Results: As of June 2006, 84 pts have enrolled. Demographic data are available from 79 pts: median age 71 years (range 47–87); sex (52 male, 27 female); ethnicity (74 Caucasian, 2 Black, 2 Hispanic, 1 Oriental); and IPSS Risk Group (Low: 22 pts; Int-1: 56 pts). Iron status is summarized in the table: Parameter n Mean ± SD Median Range Normal range n/a, not applicable Serum ferritin,μg/L 84 3779 ± 4070 2951 1160–36280 12–370 Serum iron, μg/dL 84 205 ± 64 201 48–409 37–180 Transferrin, mg/dL 82 153 ± 31 152 83–244 190–375 Transferrin saturation, % 83 85 ± 15 91 20–94 15–50 LPI, μmol/L 38 0.52 ± 0.63 0.25 0–2.9 0 Total transfusions, n 78 63.3 ± 66.3 41.5 14–435 n/a Years of transfusion 75 3.4 ± 1.9 3 1–12 n/a Baseline concurrent therapies: 5-azacytidine (Vidaza): 5 pts; lenalidomide (Revlimid): 1 pt. Calculated creatinine clearance: normal (&gt;80 mL/min): 37 pts; mildly abnormal (51–80 mL/min): 30 pts; moderately abnormal (30–50 mL/min): 9 pts. Hematological parameters: Anemia was present in all pts; other cytopenias included: neutropenia (&lt;1800/μL): 13 pts, thrombocytopenia (&lt;100,000/μL): 15 pts; neutropenia and thrombocytopenia: 12 pts. A total of 53 pts had received chelation prior to enrolling: 51 deferoxamine (Desferal®); and 2 deferasirox. Conclusions: Despite the prior availability of deferoxamine, these baseline data demonstrate significant levels of iron overload among transfused pts with myelodysplasia. Serum iron, ferritin and LPI are all well above the clinically significant thresholds associated with increased complications. Since recent data has suggested that iron overload may be a poor prognostic indicator in MDS, increased attention to maintaining appropriate iron balance is warranted. The recent availability of an oral iron chelator may be more acceptable to MDS pts and their physicians. This ongoing trial is designed to assess the long-term efficacy, safety, and clinical benefits of deferasirox in pts with MDS.

Background: Spontaneous osteonecrosis of the knee has recently been termed subchondral insufficiency fracture of the knee (SIFK) to appropriately recognize the etiology of mechanical overloading of the subchondral bone. The purpose of this study was to assess clinical outcomes of SIFK based on progression to surgical treatment and arthroplasty, and to evaluate the risk factors that increase the progression to arthroplasty. Methods: A retrospective review was performed on patients with a diagnosis of SIFK, as confirmed with use of magnetic resonance images (MRIs). Baseline and final radiographs were reviewed. Baseline MRIs were also reviewed for injury characteristics. Failure was defined as progression to surgical treatment or conversion to arthroplasty. Results: Two hundred twenty-three patients (71% female) with a mean age of 65.1 years were included. SIFK affected 154 femora (69%) and 123 tibiae (55%), with medial compartment involvement in 198 knees (89%); 74% of medial menisci had root or radial tears, with a mean extrusion of 3.6 mm. Varus malalignment was identified in 54 (69%) of 78 knees. Seventy-six (34%) of all patients progressed to surgical intervention at 2.7 years, and 66 (30%) underwent arthroplasty at 3.0 years. The rates of conversion to surgical intervention and arthroplasty increased to 47% (37 of 79; p = 0.04) and 37% (29 of 79; p = 0.09), respectively, in patients with >5 years of follow-up. The 10-year survival rate free of arthroplasty for patients with SIFK on the medial femoral condyle (p < 0.01), SIFK on the medial tibial plateau (p < 0.01), medial meniscal extrusion (p = 0.01), varus alignment (p = 0.02), and older age (per year older; p = 0.003) was significantly higher than the survival rates of those without each respective condition. Conclusions: Subchondral insufficiency fractures predominantly involve the medial compartment of the knee and commonly present with medial meniscal root and radial tears. Approximately one-third of patients progressed to total knee arthroplasty. Baseline arthritis, older age, location of the insufficiency fracture on both the medial femoral condyle and medial tibial plateau, meniscal extrusion, and varus malalignment were all associated with progression to arthroplasty. Level of Evidence: Prognostic Level IV . See Instructions for Authors for a complete description of levels of evidence.

Abstract Background: Tumor-associated macrophages have been shown to play a critical role in metastasis, angiogenesis, and immune escape. Cancer associated macrophage-like cells (CAMLs) are circulating stromal cell with macrophage expression subtypes, detected in the peripheral blood of patients with solid tumors. We have previously shown that enlargement of CAML cells is an independent predictor of poorer overall survival and an indication of progression in patients with metastatic breast cancer (MBC). However changes in CAML sizes after induction of therapy has not been investigated. Here we evaluated the association between early changes in numbers and sizes of CAMLs as it relates to clinical response after induction of new therapy. Method: Peripheral blood samples from 29 patients with metastatic breast cancer who failed at least 2 prior lines of therapies were prospectively collected. Baseline (BL) blood samples were taken prior to initiation of a new therapy and the second samples (T1) were taken approximately 30 days after initiation of a new systemic therapy. Blood samples were filtered using CellSieveTM filtration. The quantity and size of CAMLs were measured then compared between the BL and T1 time points. Univariate analysis was used to determine the association of changes in CAML numbers and changes in CAML size, with objective response at the first follow up CT scan with progression free survival (PFS). Results: CAMLs were detected in 97% of BL samples (averaging 20.9 CAMLs/7.5ml blood) and 93% of T1 samples (averaging 18.5 CAMLs/7.5mL blood). At the time of the first follow up CT scan, 17 of 29 patients (58.6%) had progressive disease based on the RECIST criteria. Among those, 14 of 17 patients (82%) had an increase in CAML size (~85% overall enlargement) and 3/17 (18%) had a decrease CAML size (~60% overall shrinkage) in T1 samples compared to baseline. In contrast, 10 of 12 patients (83%) with clinical benefit, including stable disease and partial or complete response, had a 92% reduction in their CAML’s size and 2 of 12 patients (17%) had 61% enlargement in their CAML’s size after treatment. Overall, CAML size change after therapy induction was 83% accurate in predicting clinical benefit based on subsequent scans. Furthermore, patients with enlarging CAML size at T1 had significantly shorter PFS of 4 months compared to 10 months in patients with decreasing CAML size (HR 3.7; 95%CI1.5-10.1; p 0.020). Conclusion: CAMLs can be commonly found in most treatment-refractory metastatic breast cancer patients and their morphological size is clinically correlated to poorer survival. Our data suggests that monitoring the size changes of a patient’s CAMLs after 30 days of new treatment initiation may predict clinical benefit earlier than conventional scans and act as real time monitoring of MBCs response to new therapies. Additional studies are currently ongoing to validate these results. Citation Format: Saranya Chumsri, Markus D. Lacher, William V. Williams, R. K. Alpaugh, Stuart S. Martin, Rena Lapidus, Cha-Mei Tang, Massimo Cristofanilli, Daniel L Adams. Circulating cancer associated macrophage-like cells (CAMLs) are early predictors of response to new line therapies in metastatic breast cancer [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P5-06-27.