Generating Real-World Tumor Burden Endpoints from Electronic Health Record Data: Comparison of RECIST, Radiology-Anchored, and Clinician-Anchored Approaches for Abstracting Real-World Progression in Non-Small Cell Lung Cancer.

INTRODUCTION: Real-world evidence derived from electronic health records (EHRs) is increasingly recognized as a supplement to evidence generated from traditional clinical trials. In oncology, tumor-based Response Evaluation Criteria in Solid Tumors (RECIST) endpoints are standard clinical trial metrics. The best approach for collecting similar endpoints from EHRs remains unknown. We evaluated the feasibility of a RECIST-based methodology to assess EHR-derived real-world progression (rwP) and explored non-RECIST-based approaches. METHODS: In this retrospective study, cohorts were randomly selected from Flatiron Health's database of de-identified patient-level EHR data in advanced non-small cell lung cancer. A RECIST-based approach tested for feasibility (N = 26). Three non-RECIST approaches were tested for feasibility, reliability, and validity (N = 200): (1) radiology-anchored, (2) clinician-anchored, and (3) combined. Qualitative and quantitative methods were used. RESULTS: A RECIST-based approach was not feasible: cancer progression could be ascertained for 23% (6/26 patients). Radiology- and clinician-anchored approaches identified at least one rwP event for 87% (173/200 patients). rwP dates matched 90% of the time. In 72% of patients (124/173), the first clinician-anchored rwP event was accompanied by a downstream event (e.g., treatment change); the association was slightly lower for the radiology-anchored approach (67%; 121/180). Median overall survival (OS) was 17 months [95% confidence interval (CI) 14, 19]. Median real-world progression-free survival (rwPFS) was 5.5 months (95% CI 4.6, 6.3) and 4.9 months (95% CI 4.2, 5.6) for clinician-anchored and radiology-anchored approaches, respectively. Correlations between rwPFS and OS were similar across approaches (Spearman's rho 0.65-0.66). Abstractors preferred the clinician-anchored approach as it provided more comprehensive context. CONCLUSIONS: RECIST cannot adequately assess cancer progression in EHR-derived data because of missing data and lack of clarity in radiology reports. We found a clinician-anchored approach supported by radiology report data to be the optimal, and most practical, method for characterizing tumor-based endpoints from EHR-sourced data. FUNDING: Flatiron Health Inc., which is an independent subsidiary of the Roche group.

Validation of International Classification of Diseases coding for bone metastases in electronic health records using technology-enabled abstraction.

OBJECTIVE: The accuracy of bone metastases diagnostic coding based on International Classification of Diseases, ninth revision (ICD-9) is unknown for most large databases used for epidemiologic research in the US. Electronic health records (EHR) are the preferred source of data, but often clinically relevant data occur only as unstructured free text. We examined the validity of bone metastases ICD-9 coding in structured EHR and administrative claims relative to the complete (structured and unstructured) patient chart obtained through technology-enabled chart abstraction. PATIENTS AND METHODS: Female patients with breast cancer with ≥1 visit after November 2010 were identified from three community oncology practices in the US. We calculated sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) of bone metastases ICD-9 code 198.5. The technology-enabled abstraction displays portions of the chart to clinically trained abstractors for targeted review, thereby maximizing efficiency. We evaluated effects of misclassification of patients developing skeletal complications or treated with bone-targeting agents (BTAs), and timing of BTA. RESULTS: Among 8,796 patients with breast cancer, 524 had confirmed bone metastases using chart abstraction. Sensitivity was 0.67 (95% confidence interval [CI] =0.63-0.71) based on structured EHR, and specificity was high at 0.98 (95% CI =0.98-0.99) with corresponding PPV of 0.71 (95% CI =0.67-0.75) and NPV of 0.98 (95% CI =0.98-0.98). From claims, sensitivity was 0.78 (95% CI =0.74-0.81), and specificity was 0.98 (95% CI =0.98-0.98) with PPV of 0.72 (95% CI =0.68-0.76) and NPV of 0.99 (95% CI =0.98-0.99). Structured data and claims missed 17% of bone metastases (89 of 524). False negatives were associated with measurable overestimation of the proportion treated with BTA or with a skeletal complication. Median date of diagnosis was delayed in structured data (32 days) and claims (43 days) compared with technology-assisted EHR. CONCLUSION: Technology-enabled chart abstraction of unstructured EHR greatly improves data quality, minimizing false negatives when identifying patients with bone metastases that may lead to inaccurate conclusions that can affect delivery of care.

Definitive high-dose photon/proton radiotherapy for unresected mobile spine and sacral chordomas.

STUDY DESIGN: A retrospective review. OBJECTIVE: The purpose of this study is to report the results of high-dose proton based definitive radiotherapy for unresected spinal chordomas. SUMMARY OF BACKGROUND DATA: Spine chordoma is treated primarily by surgical resection. However, local recurrence rate is high. Adjuvant radiotherapy improves local control. In certain locations, such as high sacrum, resection may result in significant neurological dysfunction. METHODS: We retrospectively reviewed 24 patients with newly diagnosed, previously untreated spinal chordomas (core biopsy only; no prior incision or resection) treated with high-dose definitive radiotherapy alone using protons and photons at our center from 1988 to 2009. RESULTS: Reasons for radiotherapy alone included medical inoperability (3) and concern for neurological dysfunction based on spine level (21). Median age was 69.5 years. Tumor locations included cervical (2), thoracic (1), lumbar (2), S1-S2 (17), and S3 or below (2). Median maximal tumor diameter was 6.6 cm (1.4-25.5), and median tumor volume was 198.3 cm (4.65-2061). Median total dose was 77.4 GyRBE (proton dose unit, gray relative biological effectiveness). Analysis at median follow-up of 56 months showed overall survival of 91.7% and 78.1%, chordoma specific survival of 95.7% and 81.5%, local progression free survival of 90.4% and 79.8% and metastases free survival of 86.5% and 76.3%, at 3 and 5 years respectively. Tumor volume more than 500 cm was correlated with worse overall survival. Long-term side effects included 8 sacral insufficiency fractures (none required surgical stabilization), 1 secondary malignancy, 1 foot drop, 1 erectile dysfunction, 1 perineal numbness, 2 worsening urinary/fecal incontinence, and 4 grade-2 rectal bleeding. None required new colostomy. All surviving patients remained ambulatory. CONCLUSION: These results support the use of high-dose definitive radiotherapy for patients with medically inoperable or otherwise unresected, mobile spine or sacrococcygeal chordomas.

Influence of culture medium on smooth muscle cell differentiation from human bone marrow-derived mesenchymal stem cells.

Human bone marrow-derived mesenchymal stem cells (hMSCs) represent an appealing source of smooth muscle cells (SMCs) for engineering small-diameter vascular grafts due to the limited availability and replicative capacity of somatic SMCs. However, lack of standardization of hMSC culture conditions has limited some progress in hMSC research. Because, at the moment, a chemically defined, serum-free medium without growth factors is not capable of amplifying hMSCs in vitro, the usage of serum (either human serum or fetal bovine serum [FBS]) continues in hMSC research. The emergence of commercial hMSCs and hMSC media opened a series of questions regarding the compatibility of commercial and homemade hMSCs and hMSC media. In this study, two types of commonly used FBS-containing hMSC media-MSCGM (containing 10% FBS) and MesenPro (containing 2% FBS), along with our homemade medium (low-glucose Dulbecco's modified Eagle's medium plus 10% selected lot FBS)-were compared in their ability to support SMC differentiation from hMSCs. The effects of FBS level, medium supplements (ascorbic acid, copper, etc.), and growth factors (transforming growth factor beta1) were also examined for their impact on SMC differentiation. It was discovered that MesenPro and transforming growth factor beta1 are the strongest SMC inducers from hMSCs. In contrast, hMSCs grown in homemade (10% Dulbecco's modified Eagle's medium) and commercial MSCGM media remained undifferentiated. FBS concentration did not affect SMC differentiation when 10% FBS was compared with 2%. Finally, the mechanism underlying SMC differentiation from hMSCs grown in FBS-containing medium was explored by following the expression changes of serum response factor during the establishment of hMSC culture.