The 21st Century Cures Act passed by the United States Congress mandates the US Food and Drug Administration to develop guidance to evaluate the use of real‐world evidence (RWE) to support the regulatory process. RWE has generated important medical discoveries, especially in areas where traditional clinical trials would be unethical or infeasible. However, RWE suffers from several issues that hinder its ability to provide proof of treatment efficacy at a level comparable to randomized controlled trials. In this review article, we summarized the advantages and limitations of RWE, identified the key opportunities for RWE, and pointed the way forward to maximize the potential of RWE for regulatory purposes.

One of the primary tools that researchers use to predict risk is the case-control study. We identify a flaw, temporal bias, that is specific to and uniquely associated with these studies that occurs when the study period is not representative of the data that clinicians have during the diagnostic process. Temporal bias acts to undermine the validity of predictions by over-emphasizing features close to the outcome of interest. We examine the impact of temporal bias across the medical literature, and highlight examples of exaggerated effect sizes, false-negative predictions, and replication failure. Given the ubiquity and practical advantages of case-control studies, we discuss strategies for estimating the influence of and preventing temporal bias where it exists.

Background Admissions are generally classified as COVID-19 hospitalizations if the patient has a positive SARS-CoV-2 polymerase chain reaction (PCR) test. However, because 35% of SARS-CoV-2 infections are asymptomatic, patients admitted for unrelated indications with an incidentally positive test could be misclassified as a COVID-19 hospitalization. Electronic health record (EHR)–based studies have been unable to distinguish between a hospitalization specifically for COVID-19 versus an incidental SARS-CoV-2 hospitalization. Although the need to improve classification of COVID-19 versus incidental SARS-CoV-2 is well understood, the magnitude of the problems has only been characterized in small, single-center studies. Furthermore, there have been no peer-reviewed studies evaluating methods for improving classification. Objective The aims of this study are to, first, quantify the frequency of incidental hospitalizations over the first 15 months of the pandemic in multiple hospital systems in the United States and, second, to apply electronic phenotyping techniques to automatically improve COVID-19 hospitalization classification. Methods From a retrospective EHR-based cohort in 4 US health care systems in Massachusetts, Pennsylvania, and Illinois, a random sample of 1123 SARS-CoV-2 PCR-positive patients hospitalized from March 2020 to August 2021 was manually chart-reviewed and classified as “admitted with COVID-19” (incidental) versus specifically admitted for COVID-19 (“for COVID-19”). EHR-based phenotyping was used to find feature sets to filter out incidental admissions. Results EHR-based phenotyped feature sets filtered out incidental admissions, which occurred in an average of 26% of hospitalizations (although this varied widely over time, from 0% to 75%). The top site-specific feature sets had 79%-99% specificity with 62%-75% sensitivity, while the best-performing across-site feature sets had 71%-94% specificity with 69%-81% sensitivity. Conclusions A large proportion of SARS-CoV-2 PCR-positive admissions were incidental. Straightforward EHR-based phenotypes differentiated admissions, which is important to assure accurate public health reporting and research.

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The International Classification of Diseases (ICD)-10 code (U09.9) for post-acute sequelae of COVID-19 (PASC) was introduced in October of 2021. As researchers seek to leverage this billing code for research purposes in large scale real-world studies of PASC, it is of utmost importance to understand the functional use of the code by healthcare providers and the clinical characteristics of patients who have been assigned this code. To this end, we operationalized clinical case definitions of PASC using World Health Organization and Centers for Disease Control guidelines. We then chart reviewed 300 patients with COVID-19 from three participating healthcare systems of the 4CE Consortium who were assigned the U09.9 code. Chart review results showed the average positive predictive value (PPV) of the U09.9 code ranged from 40.2% to 65.4% depending on which definition of PASC was used in the evaluation. The PPV of the U09.9 code also fluctuated significantly between calendar time periods. We demonstrated the potential utility of textual data extracted from natural language processing techniques to more comprehensively capture symptoms associated with PASC from electronic health records data. Finally, we investigated the utilization of long COVID clinics in the cohort of patients. We observed that only an average of 24.0% of patients with the U09.9 code visited a long COVID clinic. Among patients who met the WHO PASC definition, only an average of 35.6% visited a long COVID clinic.

To date, because of their rarity, the clinicopathological features and surgical outcomes of small bowel adenocarcinomas (SBAs) have been insufficiently explored. We evaluated the clinicopathological features and long-term outcomes of patients who underwent surgery for SBA.This retrospective study (from 1999 to 2016) examined patients with SBA treated surgically at the China National Cancer Center/Cancer Hospital. Clinicopathological features, preoperative evaluation, surgical treatment, and outcome parameters were reviewed and analyzed.Among the 241 patients studied, pancreaticoduodenectomies were performed in 51.0%, partial resection in 24.5%, palliative bypass surgery in 23.7%, and abdominal exploration in 0.8% of the patients. Majority of the patients were diagnosed at an advanced disease stage, and the duodenum was the most common tumor site. Postoperative complications occurred in 44.4% of the patients. Median overall and progression-free survival rates were 22.0 and 13.0 months, respectively. The 5-year overall and progression-free survival rates for patients with duodenal adenocarcinoma were 30.2% and 21.7%, respectively. Duodenal adenocarcinomas, lymph node metastases, distant metastases, poor differentiation, and lymphovascular invasion were associated with poor overall survival outcomes. The 3 factors associated with progression-free survival were the degree of differentiation, lymph node metastases, and distant metastases.Surgery remains the mainstay of treatment for SBA. A poor prognosis could be owing to the site, metastasis, differentiation, and lymphovascular invasion; however, the prognosis may improve through early diagnosis and operation.

Surgery is the mainstay of treatment for small bowel tumors. Adenocarcinomas and duodenal involvement seem to contribute to poor outcomes.

Rationale:Perivascular epithelial cell tumors (PEComas) of the pancreas are rare mesenchymal tumors and, to our knowledge, only 20 cases have been reported to date.Patient concerns:We report a 43-year-old female who presented with upper abdominal pain for 1 year. She underwent an exploratory laparotomy at a local hospital, which failed to resect the tumor. Five months later, she came to the Chinese National Cancer Center for surgery. Preoperative imaging revealed an 11.5-cm-sized mass located in the head of the pancreas. At the microscopic level, the tumor was composed of epithelioid and spindle cells possessing clear to focally granular eosinophilic cytoplasm, which grew in a nested and alveolar pattern around blood vessels. The tumor cells showed immunoreactivity for human melanoma black 45 (HMB-45), but did not express epithelial or endocrine markers.Diagnoses:Pancreatic PEComa.Interventions:Pancreaticoduodenectomy, partial hepatectomy, and vascular replacement were performed. After the surgery, the patient received 4 cycles of chemotherapy.Outcomes:The patient is free of recurrence and metastasis 1.5 years after surgical resection.Lessons:PEComa should be recognized as a preoperative differential diagnosis of pancreatic tumors. For treatment, removal of the tumor should be attempted, and in the case of tumors with malignant tendencies, the addition of chemotherapy should be considered.