Citations

Background: Database research is being used in orthopaedic literature with increased regularity. The main limitation of database research is the absence of diagnosis and treatment verification afforded by medical chart review. This absence may limit the accuracy of some conclusions and recommendations produced by database research. Hypothesis/Purpose: The purpose was to describe the accuracy of 1 database (Rochester Epidemiology Project) used in orthopaedic research to detect isolated anterior cruciate ligament (ACL) tears and to discuss the limitations of database research. It was hypothesized that diagnostic codes alone are unlikely to be accurate in identifying patients with ACL tears. Study Design: Cohort study (diagnosis); Level of evidence, 2. Methods: A population-based historical cohort study was performed with the Rochester Epidemiology Project database. All subjects had International Classification of Diseases, Ninth Revision, diagnosis codes consistent with ACL tears between January 1, 1990, and December 31, 2010. The medical records of all subjects were reviewed in detail to confirm the accuracy of diagnosis and gather data on injury type, laterality, associated meniscal injuries, magnetic resonance imaging findings, and treatment details. Results: A total of 3494 patients had codes consistent with ACL tears, and 2288 of them were confirmed through chart review to have an isolated ACL tear (65.5%). Among these were 1841 patients (52.7%) with an ACL tear within 1 year of injury and an additional 447 (12.8%) with an ACL tear >1 year from injury. Thirty-nine patients (1.1%) had a partial ACL tear diagnosed on magnetic resonance imaging, 48 (1.4%) had an isolated posterior cruciate ligament tear, and 22 (0.6%) had a combined ACL–posterior cruciate ligament injury. Twenty-four patients (0.7%) had ACL reconstruction before the study period. The remaining 1073 patients (30.7%) had diagnostic codes consistent with an ACL tear but did not have a cruciate ligament injury. Conclusion: This study demonstrates low accuracy with the use of diagnostic codes alone to identify an ACL tear. Database studies offer unique benefits to the medical literature, but the inherent limitations should be taken into account when these data are used to counsel patients, dictate clinical management, or make health care policy decisions. Information from a health care database is most accurate when accompanied by verification of diagnosis, treatment, and outcomes with medical chart review.

Abstract Background: Blood-based biomarkers (PSA, CEA, CA125) are used to track real-time progression of disease in parallel with imaging. However, while numerous blood biomarkers exist, they are specific to cancer type (i.e., PSA to prostate and CEA to colon) and may not appear in all diseased individuals. Recently, cancer-associated macrophage-like cells (CAMLs), a circulating stromal cell subtype, were identified in various solid cancer types, which were observed increasing in size and in hyperploidy during progressive disease. To assess whether CAML enlargement is a biomarker of progression/response, we tracked CAML growth/shrinkage in a pilot study of patients (n=34). Blood was drawn from patients with lung, prostate, or breast cancers over a 3-month period, baseline through 2 treatment cycles, followed by continued monitoring for 2 years. These data suggest that morphologic assessment of CAMLs (growth/hyperploidy) appear to parallel cancer progression, or response to treatment, in multiple solid tumors. Methods: A prospective multi-institutional study used anonymized peripheral blood samples from 34 cancer patients undergoing therapy [stage I (n=2), II (n=3), III (n=8) & IV (n=21)] with breast (n=10), lung (n=16), & prostate (n=8). Samples were taken prior to therapy (BL), at 1 month (FU1) follow-up and a 3-month (FU2) follow-up, after induction of therapy. Blood was processed by the CellSieve™ microfiltration technique at 4 institutions and stained for cytokeratin 8, 18 and 19, CD14 and CD45. After identification and quantification, CAMLs were measured based on their hyperploidy and cell size. Results: CAMLs were found in 97% of cancer patients at BL, 97% at FU1 and 91% of FU2. Over the 2-year follow-up, 7 patients showed no signs of clinical disease progression, while 27 patients had observable progression. Of the 7 patients who did not progress, only two had CAMLs of ≥50µm at BL and at FU1, but whose CAMLs shrunk to <50 µm by FU2. Of the 27 patients who progressed, 22 patients had ≥50µm CAMLs at all time points, while 5 patients had small <50µm CAMLs at BL. Interestingly, CAMLs in these 5 patients had enlarged to ≥50µm by the FU2 time point. Conclusions: We show that increased polynucleation and CAML enlargement indicate shorter progression-free survival in a number of cancer types after baseline. By monitoring CAML changes over time for the 34 individual patients, we demonstrated correlation of ongoing progression, or response, in tumors to the enlargement or shrinkage in CAMLs at follow-up time points from treatment induction. This pilot study suggests that CAMLs have the potential to monitor the progression/regression of malignancy in real time and suggests the need for larger validation studies. Citation Format: Daniel L. Adams, Raymond Bergan, Martin J. Edelman, Stuart S. Martin, Rena Lapidus, Saranya Chumsri, Cha-Mei Tang, Steven H. Lin. Real-time monitoring of solid tumor progression by circulating stromal cells from early- to late-stage disease [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 1560.

Abstract Background: We previously demonstrated that cancer associated macrophage-like cells (CAMLs) are cancer specific giant polyploid cells circulating in the blood of patients with solid tumors. Building on our initial discovery, others have shown that these hyperploidy cells are an innate immune response that is associated with decreased survival. However to date, no studies have been done to elucidate their clinical significance as in relation to the various stages of malignant disease. We established a 4 year prospective study of 315 patients from a variety of solid tumors (breast, prostate, lung, renal cell, pancreas, and esophageal) comparing the morphological properties of CAMLs in both early and late stage disease as they relate to progression free and overall survival (PFS/OS). These data suggest that CAML size appears have a strong negative correlation with progression and survival of cancer patients, irregardless of stage of disease, indicating their possible use as a non-invasive blood based biomarker in solid tumors. Methods: A prospective multi-institutional study used anonymized peripheral blood from 315 cancer patients [stage I (n=62), stage II (n=72), stage III (n=69) & stage IV (n=106)] from subjects with breast (n=59), esophageal (n=27), lung (n=59), renal cell carcinoma (n=37), prostate (n=74), pancreas cancers (n=59). CAMLs were isolated by the CellSieve™ microfiltration technique at 5 institutions and stained for cytokeratin 8, 18, & 19, CD14 and CD45. After imaging, a size based threshold ≥50µm was used to separate the patient cohorts, based on previously published assessments. Results: At least one CAML was found in 92% of cancer patients (n=289/315), with the lowest sensitivity in stage 1 (86%), followed by stage 2 (90%), stage 3 (97%) and stage 4 (95%). The property of CAML size was then evaluated. Overall, CAMLs of <50µm in size had superior PFS (HR: 3.8; 95% CI 2.8-5.3; p<0.001) and OS (HR=3.8; 95% CI 2.6-5.7;p<0.001) than those with ≥50 µm CAMLs. By each stage individually, stage 1 (PFS HR=7.5; 95% CI 3.2-17.7; p<0.001), stage II (PFS; HR=4.1; 95% CI 1.9-8.8; p<0.001), stage III (PFS HR=3.1; 95% CI 1.7-5.7; p=0.007), and stage IV (PFS HR=2.7; 95% CI 1.6-4.4; p<0.001). Conclusions: In this first large scale prospective study of the clinical utility of CAMLs, it appears that they are present in every stages of invasive solid tumor malignancies, with prevalence increasing with stage. Interestingly decreased CAML size was found to be associated with improved outcome and longer PFS. These data suggest that CAML detection and size assessment constitute a new real time predictor of progression, and survival in both early and late stage disease indicating the need for additional validation studies. Citation Format: Daniel L. Adams, Steven H. Lin, R. Katherine Alpaugh, Thai Ho, Jeffrey R. Marks, Stuart S. Martin, Susan Tsai, Saranya Chumsri, Cha-Mei Tang, Massimo Cristofanilli, Raymond Bergan. Cancer associated macrophage-like (CAMLs) cells in blood predict progression and survival for all stages of solid tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 2631.

Abstract Background Chronic pancreatitis (CP) patients frequently experience malabsorption and maldigestion, leading to micronutrient and macronutrient deficiencies. Comorbid diabetes and lifestyle habits, such as alcohol consumption, may impact nutrition status. Methods We compared micronutrient antioxidant, bone metabolism, serum protein, and inflammatory marker levels in 301 CP patients and 266 controls with no known pancreatic disease. We analyzed serum prealbumin and retinol binding protein; vitamins A, D, E, and B12; osteocalcin; tumor necrosis factor‐α; and C‐reactive protein (CRP). We also evaluated biomarkers among subsets of patients, examining factors including time since diagnosis, body mass index, alcohol as primary etiology, diabetes mellitus, vitamin supplementation, and pancreatic enzyme replacement. Results After correcting for multiple comparisons, CP patients had significantly lower levels than controls of the following: vitamin A (40.9 vs 45.4 μg/dL) and vitamin E (α‐tocopherol [8.7 vs 10.3 mg/L] and γ‐tocopherol [1.8 vs 2.2 mg/L]), as well as osteocalcin (7.9 vs 10 ng/mL) and serum prealbumin (23 vs 27 mg/dL). Both patients and controls who took vitamin supplements had higher serum levels of vitamins than those not taking supplements. Compared with controls, in controlled analyses, CP patients had significantly lower levels of vitamins A, D, and E (both α‐tocopherol and γ‐tocopherol). CP patients also had significantly lower levels of osteocalcin, serum prealbumin, and retinol binding protein, and higher CRP. Conclusions CP patients demonstrated lower levels of selected nutrition and bone metabolism biomarkers than controls. Diabetes and alcohol did not impact biomarkers. Vitamin supplements and pancreatic enzyme replacement therapy improved nutrition biomarkers in CP patients.

Background: Full-thickness radial meniscal tears render the meniscus nonfunctional and have historically been treated with partial meniscectomy. As preservative techniques evolve for radial repair, comparisons with other tear patterns are necessary to evaluate repair efficacy and prognosis. Purpose: To assess clinical outcomes and reoperation rates of radial meniscal repair and to compare them to bucket-handle meniscal repair. Study Design: Cohort study; Level of evidence, 3. Methods: Radial and bucket-handle meniscal tears without concurrent root injuries undergoing surgical repair at a single institution between 2007 and 2015 were analyzed, including both all-inside and inside-out suturing techniques. Propensity matching was performed on the basis of age at surgery, sex, meniscus laterality, body mass index (BMI), and concomitant anterior cruciate ligament reconstruction (ACLR) using a comparison pool of 70 bucket-handle repairs. Reoperation-free survival rates and Tegner, visual analog scale (VAS) for pain, and International Knee Documentation Committee (IKDC) scores were analyzed. Results: Twenty-four patients (18 male, 6 female; mean age, 22.8 ± 11.9 years) who underwent repair of a radial meniscal tear were followed for a mean of 3.5 years (range, 2.0-6.3 years). Significant postoperative improvements in VAS scores at rest and with use and IKDC scores were noted postoperatively ( P < .001). Five patients (20.8%) required a reoperation. Subsequently, 18 patients with radial tears (mean age, 19.1 ± 9.1 years; 12 male; mean BMI, 27.0 ± 6.2 kg/m 2 ; 3 medial; 11 ACLR) were propensity matched to 18 patients with bucket-handle tears (mean age, 20.8 ± 5.1 years; 13 male; mean BMI, 25.0 ± 3.5 kg/m 2 ; 3 medial; 11 ACLR). The matched radial and bucket-handle groups demonstrated similar ( P = .17) reoperation-free survival rates at 2 years (88.9% and 94.4%, respectively) and 5 years (77.8% and 87.7%, respectively). VAS and IKDC scores improved significantly after surgery ( P < .001), with no difference noted between the groups ( P ≥ .17). Patients with radial and bucket-handle meniscal repairs achieved mean postoperative Tegner scores (6.6 and 6.6, respectively) not significantly different from their preinjury levels (6.9 and 6.7, respectively) ( P ≥ .32). Conclusion: Satisfactory clinical outcomes are achievable for radial meniscal tear repair at short-term follow-up. In a robustly matched comparison, radial and bucket-handle meniscal tears demonstrate similar improvements in VAS and IKDC scores, restoration of preoperative Tegner scores, and acceptable reoperation rates. Full-thickness radial meniscal tears should be considered for repair.