Faculty Bibliography

BACKGROUND:Current NCCN guidelines exclude the possibility of using single-agent adjuvant chemotherapy in locally advanced gastric adenocarcinoma, while allowing doublet chemotherapy. However, single-agent adjuvant chemotherapy is a valid treatment option in other gastrointestinal malignancies, preferred for elderly and/or frail patients. The current study used a nationwide oncology database to assess the benefit of single-agent adjuvant chemotherapy, specifically in the elderly population. METHODS:Using the National Cancer Database (2004-2016) we identified 1953 individuals with non-metastatic gastric adenocarcinoma who underwent upfront D2 gastrectomy with pathologic stage ≥ T3 or Npos and free surgical margins, and had not received either preoperative chemotherapy or pre-/postoperative radiotherapy. We used IPTW analysis to compare overall survival between individuals receiving either single- or multi-agent adjuvant chemotherapy, or referred to observation alone. RESULTS:Individuals receiving single-agent chemotherapy had an overall survival benefit compared with observation alone, with an HR of 0.70 (95% CI 0.55-0.88, p < 0.001). Individuals over the age of 65 had an OS benefit with an HR of 0.61 (95% CI 0.46-0.82, p < 0.001). Comparing individuals over the age of 65 receiving single- vs. multi-agent chemotherapy, there was no overall survival difference with an HR of 0.87 (95% CI 0.64-1.18, p = 0.38). CONCLUSIONS:Single-agent adjuvant chemotherapy with a fluoropyrimidine in locally advanced gastric adenocarcinoma following D2 gastrectomy can improve overall survival in elderly patients. Clinicians may consider using either capecitabine or 5-FU as a treatment option in the adjuvant setting for this age group.

BACKGROUND:Natural language processing (NLP) offers significantly faster variable extraction compared to traditional human extraction but cannot interpret complicated notes as well as humans can. Thus, we hypothesized that an "NLP-assisted" extraction system, which uses humans for complicated notes and NLP for uncomplicated notes, could produce faster extraction without compromising accuracy. OBJECTIVE:The aim of this study was to develop and pilot an NLP-assisted extraction system to leverage the strengths of both human and NLP extraction of prostate cancer Gleason scores. METHODS:We collected all available clinical and pathology notes for prostate cancer patients in an unselected academic biobank cohort. We developed an NLP system to extract prostate cancer Gleason scores from both clinical and pathology notes. Next, we designed and implemented the NLP-assisted extraction system algorithm to categorize notes into "uncomplicated" and "complicated" notes. Uncomplicated notes were assigned to NLP extraction and complicated notes were assigned to human extraction. We randomly reviewed 200 patients to assess the accuracy and speed of our NLP-assisted extraction system and compared it to NLP extraction alone and human extraction alone. RESULTS:Of the 2051 patients in our cohort, the NLP system extracted a prostate surgery Gleason score from 1147 (55.92%) patients and a prostate biopsy Gleason score from 1624 (79.18%) patients. Our NLP-assisted extraction system had an overall accuracy rate of 98.7%, which was similar to the accuracy of human extraction alone (97.5%; P=.17) and significantly higher than the accuracy of NLP extraction alone (95.3%; P<.001). Moreover, our NLP-assisted extraction system reduced the workload of human extractors by approximately 95%, resulting in an average extraction time of 12.7 seconds per patient (vs 256.1 seconds per patient for human extraction alone). CONCLUSIONS:We demonstrated that an NLP-assisted extraction system was able to achieve much faster Gleason score extraction compared to traditional human extraction without sacrificing accuracy.

INTRODUCTION:The use of total neoadjuvant therapy (TNT) for locally advanced rectal cancer has been increasing in recent years, but the long-term overall survival characteristics of this approach is currently unknown. METHODS:We performed a retrospective study of patients with clinical stage II/III rectal cancer within the National Cancer Database. Patients who received TNT (defined as chemotherapy, followed by CRT, followed by surgery) were propensity score matched to patients who received adjuvant therapy (defined as CRT, followed by surgery, followed by chemotherapy). We compared overall survival (OS) and rates of pathologic complete response (pCR) between the 2 arms. RESULTS:1.00, 95% CI, 0.71-1.40, P = .99). After propensity score matching, there were higher pCR rates among TNT patients (16.1%) compared to adjuvant therapy patients (12.0%) (P = .037). CONCLUSION:In this observational study, we found TNT was not associated with a lower OS compared to standard adjuvant chemotherapy. This finding potentially reassures clinicians choosing TNT as an alternative to adjuvant chemotherapy. However, future prospective data are needed to confirm these findings.

PURPOSE/OBJECTIVE:Treatment of metastatic melanoma has dramatically improved in recent years, thanks to the development of immunotherapy and BRAF-MEK-targeted therapies. However, these developments revealed marked heterogeneity in patient response, which is yet to be fully understood. In this work, we aimed to associate the proteomic profiles of metastatic melanoma with the patient clinical information, to identify protein correlates with metastatic location and prior treatments. EXPERIMENTAL DESIGN/METHODS:status, survival, and immunotherapy response with the tumor molecular profiles. RESULTS:mutation status and prior treatments with MAPK inhibitors proposed the molecular basis of the effect on immunotherapy response and suggested coordinated combination of immunotherapy and targeted therapy may increase treatment efficacy. CONCLUSIONS:Altogether, the proteomic data provided novel molecular determinants of critical clinical features, including the effects of sequential treatments and metastatic locations. These results can be the basis for development of site-specific treatments toward treatment personalization.

The Ataxia-Telangiesctasia, mutated (ATM) gene is involved in a number of DNA damage repair pathways and confers an increased risk for pancreatic ductal adenocarcinoma (PDAC). In this retrospective study, we identified and profiled 22 patients with PDAC and a known somatic or germline pathogenic ATM alteration (case patients). These patients were matched 2:1 by age, stage, and year at diagnosis to patients with PDAC without known ATM alterations. The median overall survival in patients with ATM alterations was 40.2 months compared with 15.5 months in the control population (hazard ratio = 0.14, 95% confidence interval = 0.04 to 0.47, 2-sided P = .001). In multivariable analysis, these findings persisted after adjustment for receipt of platinum therapy and Eastern Cooperative Oncology Group status. These findings suggest that pathogenic ATM alterations may be prognostic for improved outcomes in patients with pancreatic cancer.

BACKGROUND:Scientists are developing new computational methods and prediction models to better clinically understand COVID-19 prevalence, treatment efficacy, and patient outcomes. These efforts could be improved by leveraging documented COVID-19-related symptoms, findings, and disorders from clinical text sources in an electronic health record. Word embeddings can identify terms related to these clinical concepts from both the biomedical and nonbiomedical domains, and are being shared with the open-source community at large. However, it's unclear how useful openly available word embeddings are for developing lexicons for COVID-19-related concepts. OBJECTIVE:Given an initial lexicon of COVID-19-related terms, this study aims to characterize the returned terms by similarity across various open-source word embeddings and determine common semantic and syntactic patterns between the COVID-19 queried terms and returned terms specific to the word embedding source. METHODS:We compared seven openly available word embedding sources. Using a series of COVID-19-related terms for associated symptoms, findings, and disorders, we conducted an interannotator agreement study to determine how accurately the most similar returned terms could be classified according to semantic types by three annotators. We conducted a qualitative study of COVID-19 queried terms and their returned terms to detect informative patterns for constructing lexicons. We demonstrated the utility of applying such learned synonyms to discharge summaries by reporting the proportion of patients identified by concept among three patient cohorts: pneumonia (n=6410), acute respiratory distress syndrome (n=8647), and COVID-19 (n=2397). RESULTS:We observed high pairwise interannotator agreement (Cohen kappa) for symptoms (0.86-0.99), findings (0.93-0.99), and disorders (0.93-0.99). Word embedding sources generated based on characters tend to return more synonyms (mean count of 7.2 synonyms) compared to token-based embedding sources (mean counts range from 2.0 to 3.4). Word embedding sources queried using a qualifier term (eg, dry cough or muscle pain) more often returned qualifiers of the similar semantic type (eg, "dry" returns consistency qualifiers like "wet" and "runny") compared to a single term (eg, cough or pain) queries. A higher proportion of patients had documented fever (0.61-0.84), cough (0.41-0.55), shortness of breath (0.40-0.59), and hypoxia (0.51-0.56) retrieved than other clinical features. Terms for dry cough returned a higher proportion of patients with COVID-19 (0.07) than the pneumonia (0.05) and acute respiratory distress syndrome (0.03) populations. CONCLUSIONS:Word embeddings are valuable technology for learning related terms, including synonyms. When leveraging openly available word embedding sources, choices made for the construction of the word embeddings can significantly influence the words learned.

BACKGROUND:Age and time information stored within the histories of clinical notes can provide valuable insights for assessing a patient's disease risk, understanding disease progression, and studying therapeutic outcomes. However, details of age and temporally-specified clinical events are not well captured, consistently codified, and readily available to research databases for study. METHODS:We expanded upon existing annotation schemes to capture additional age and temporal information, conducted an annotation study to validate our expanded schema, and developed a prototypical, rule-based Named Entity Recognizer to extract our novel clinical named entities (NE). The annotation study was conducted on 138 discharge summaries from the pre-annotated 2014 ShARe/CLEF eHealth Challenge corpus. In addition to existing NE classes (TIMEX3, SUBJECT_CLASS, DISEASE_DISORDER), our schema proposes 3 additional NEs (AGE, PROCEDURE, OTHER_EVENTS). We also propose new attributes, e.g., "degree_relation" which captures the degree of biological relation for subjects annotated under SUBJECT_CLASS. As a proof of concept, we applied the schema to 49 H&P notes to encode pertinent history information for a lung cancer cohort study. RESULTS:An abundance of information was captured under the new OTHER_EVENTS, PROCEDURE and AGE classes, with 23%, 10% and 8% of all annotated NEs belonging to the above classes, respectively. We observed high inter-annotator agreement of >80% for AGE and TIMEX3; the automated NLP system achieved F1 scores of 86% (AGE) and 86% (TIMEX3). Age and temporally-specified mentions within past medical, family, surgical, and social histories were common in our lung cancer data set; annotation is ongoing to support this translational research study. CONCLUSIONS:Our annotation schema and NLP system can encode historical events from clinical notes to support clinical and translational research studies.

BACKGROUND:Retrospective studies suggest a survival benefit when platinum-based chemotherapy is administered to patients with pancreatic cancer harbouring a germline mutation in BRCA1, BRCA2 or PALB2 (mut-positive PDAC). However, the objective response rate (ORR) and real-world progression free survival (rwPFS) achieved with such treatment remain ill-defined. METHODS:Twenty-six patients with advanced-stage mut-positive PDAC who had been treated with platinum-based therapy were matched by age, race and sex to 52 platinum-treated control PDAC patients. Responses to therapy were determined by RECIST v1.1, performed by blinded radiology review. Measured outcomes included ORR and rwPFS. RESULTS:The ORR in mut-positive patients was 58% compared to 21% in the control group (p = 0.0022). There was no significant difference in ORR between platinum regimens in mut-positive patients (p = 0.814), whereas in control patients, the only observed responses were to FOLFIRINOX. rwPFS was 10.1 mo. for mut-positive patients and 6.9 mo. for controls (HR 0.43; 95% CI 0.25-0.74; 0.0068). CONCLUSION:Mut-positive PDAC has a high ORR and prolonged rwPFS to platinum-based chemotherapy. These findings may have implications particularly in the neoadjuvant setting, and for future clinical trial design, and highlight the importance of early germline testing in patients with PDAC.

PURPOSE/OBJECTIVE:confer an increased risk for pancreatic ductal adenocarcinoma (PDAC). Tumors associated with mutations in homologous recombination genes are sensitive to DNA-damaging agents. We retrospectively studied patients with resected PDAC and a pathogenic germline mutation in one of these three genes. The planned analyses included overall survival (OS) and changes therein when platinum chemotherapy was used in the perioperative setting. MATERIALS AND METHODS/METHODS:and resected PDAC (mutation positive) were matched in a 1:2 fashion to patients who were noncarriers or untested (mutation negative) by age, year of diagnosis, stage, and sex. Patients were identified via one of two available databases at University of Pennsylvania: the Basser Center for BRCA Registry or the electronic medical record. The primary outcome was OS. RESULTS:= .07). CONCLUSION/CONCLUSIONS:mutation. Knowledge of a germline mutation may be important to determine best choice of perioperative chemotherapy.