Pathologist-Verified Billing: Correction Rates of Miscoded Frozen Section Cases.

CONTEXT.­: With the adoption of Epic/Beaker at our institution, surgical pathology specimens are assigned a Current Procedural Terminology (CPT) charge code at the time of accessioning, and pathologists have been made responsible for verifying the accuracy of the code before signing out the case. OBJECTIVE.­: To determine with what frequency attending pathologists reassigned the correct charge code to a specimen when the code assigned at accessioning was incorrect, as well as to estimate the potential financial impact of missed changes. DESIGN.­: We reviewed all specimens received for frozen section during a 7-month period, identified specimens where the default charge code that our departmental protocol assigns at frozen section (88305) was incorrect, and assessed the rate of successful code change by pathologists and the potential financial cost of each missed change. RESULTS.­: Three hundred fifty-two of 2191 frozen section specimens (16%) required a change in the 88305 charge code. The codes for 195 specimens (55%) were correctly changed by the attending pathologist, while 157 (45%) were not changed (149) or were changed to an incorrect charge code (8). Individual pathologist change rates ranged from 0% to 100%, with a mean and median change rate of 43% and 24%, respectively. Using average code reimbursements at our institution, the loss in revenue from the 157 missed and incorrect frozen section changes was estimated at $13 788 ($1970 per month). CONCLUSIONS.­: Pathologists showed highly variable rates of correcting CPT charge codes when the incorrect code had been previously assigned to a case, with associated loss of revenue from missed and incorrect code changes.

Complete Pathologic Response to Pembrolizumab and Axitinib in a Patient With Sarcomatoid RCC and Ocrelizumab-Treated Multiple Sclerosis.

Non-clear cell renal cell carcinoma (RCC) is a heterogeneous disease. We report a case of sarcomatoid non-clear cell RCC in a patient with underlying multiple sclerosis (MS) on immunosuppression with a complete pathologic response to pembrolizumab and axitinib. Comprehensive genomic profiling revealed pathogenic mutations in SETD2 and TP53 with high RNA expression levels of immune checkpoint proteins. Our case illustrates the importance of treatment selection based on presence of sarcomatoid features, underlying autoimmune disease, and genomic profiling.

Mutations in RABL3 alter KRAS prenylation and are associated with hereditary pancreatic cancer.

Pancreatic ductal adenocarcinoma is an aggressive cancer with limited treatment options1. Approximately 10% of cases exhibit familial predisposition, but causative genes are not known in most families2. We perform whole-genome sequence analysis in a family with multiple cases of pancreatic ductal adenocarcinoma and identify a germline truncating mutation in the member of the RAS oncogene family-like 3 (RABL3) gene. Heterozygous rabl3 mutant zebrafish show increased susceptibility to cancer formation. Transcriptomic and mass spectrometry approaches implicate RABL3 in RAS pathway regulation and identify an interaction with RAP1GDS1 (SmgGDS), a chaperone regulating prenylation of RAS GTPases3. Indeed, the truncated mutant RABL3 protein accelerates KRAS prenylation and requires RAS proteins to promote cell proliferation. Finally, evidence in patient cohorts with developmental disorders implicates germline RABL3 mutations in RASopathy syndromes. Our studies identify RABL3 mutations as a target for genetic testing in cancer families and uncover a mechanism for dysregulated RAS activity in development and cancer.

Metabolic Responses to Dietary Protein Restriction Require an Increase in FGF21 that Is Delayed by the Absence of GCN2.

FGF21 contributes to the metabolic response to dietary protein restriction, and prior data implicate GCN2 as the amino acid sensor linking protein restriction to FGF21 induction. Here, we demonstrate the persistent and essential role of FGF21 in the metabolic response to protein restriction. We show that Fgf21 KO mice are fully resistant to low protein (LP)-induced changes in food intake, energy expenditure (EE), body weight gain, and metabolic gene expression for 6 months. Gcn2 KO mice recapitulate this phenotype, but LP-induced effects on food intake, EE, and body weight subsequently begin to appear after 14 days on diet. We show that this delayed emergence of LP-induced metabolic effects in Gcn2 KO mice coincides with a delayed but progressive increase of hepatic Fgf21 expression and blood FGF21 concentrations over time. These data indicate that FGF21 is essential for the metabolic response to protein restriction but that GCN2 is only transiently required for LP-induced FGF21.

Iterative use of nuclear receptor Nr5a2 regulates multiple stages of liver and pancreas development.

The stepwise progression of common endoderm progenitors into differentiated liver and pancreas organs is regulated by a dynamic array of signals that are not well understood. The nuclear receptor subfamily 5, group A, member 2 gene nr5a2, also known as Liver receptor homolog-1 (Lrh-1) is expressed in several tissues including the developing liver and pancreas. Here, we interrogate the role of Nr5a2 at multiple developmental stages using genetic and chemical approaches and uncover novel pleiotropic requirements during zebrafish liver and pancreas development. Zygotic loss of nr5a2 in a targeted genetic null mutant disrupted the development of the exocrine pancreas and liver, while leaving the endocrine pancreas intact. Loss of nr5a2 abrogated exocrine pancreas markers such as trypsin, while pancreas progenitors marked by ptf1a or pdx1 remained unaffected, suggesting a role for Nr5a2 in regulating pancreatic acinar cell differentiation. In the developing liver, Nr5a2 regulates hepatic progenitor outgrowth and differentiation, as nr5a2 mutants exhibited reduced hepatoblast markers hnf4α and prox1 as well as differentiated hepatocyte marker fabp10a. Through the first in vivo use of Nr5a2 chemical antagonist Cpd3, the iterative requirement for Nr5a2 for exocrine pancreas and liver differentiation was temporally elucidated: chemical inhibition of Nr5a2 function during hepatopancreas progenitor specification was sufficient to disrupt exocrine pancreas formation and enhance the size of the embryonic liver, suggesting that Nr5a2 regulates hepatic vs. pancreatic progenitor fate choice. Chemical inhibition of Nr5a2 at a later time during pancreas and liver differentiation was sufficient to block the formation of mature acinar cells and hepatocytes. These findings define critical iterative and pleiotropic roles for Nr5a2 at distinct stages of pancreas and liver organogenesis, and provide novel perspectives for interpreting the role of Nr5a2 in disease.