Interrater Reliability in Toxicity Identification: Limitations of Current Standards.

PurposeThe National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE) v5.0 is the standard for oncology toxicity encoding and grading, despite limited validation. We assessed interrater reliability (IRR) in multireviewer toxicity identification.Methods and materialsTwo reviewers independently reviewed 100 randomly selected notes for weekly on-treatment visits during radiation therapy from the electronic health record. Discrepancies were adjudicated by a third reviewer for consensus. Term harmonization was performed to account for overlapping symptoms in CTCAE. IRR was assessed based on unweighted and weighted Cohen's kappa coefficients.ResultsBetween reviewers, the unweighted kappa was 0.68 (95% confidence interval, 0.65-0.71) and the weighted kappa was 0.59 (0.22-1.00). IRR was consistent between symptoms noted as present or absent with a kappa of 0.6 (0.66-0.71) and 0.6 (0.65-0.69), respectively.ConclusionsSignificant discordance suggests toxicity identification, particularly retrospectively, is a complex and error-prone task. Strategies to minimize IRR, including training and simplification of the CTCAE criteria, should be considered in trial design and future terminologies

NEDD4L protein levels are down in CRC.

<p>(A) NEDD4L levels were determined by western blotting of CRC (Ca) and adjacent normal (Nl) mucosa from twenty individuals. Levels were normalized to TUBA and Nl was compared to Ca. NEDD4L was significantly downregulated (∼42%) in CRC (*p<0.05). Data is represented in box and whisker plot format. The lines connecting data points show the relative NEDD4L levels in a given Nl-Ca matched pair. Red denotes decreased NEDD4L levels in Ca, while black denotes an increase. (B) Lysates generated from Nl-Ca matched pairs were blotted for NEDD4L and TUBA. Shown here are four representative pairs.</p

The NEDD4 family of E3 ubiquitin ligases.

<p>The nine members of the NEDD4 family are modular proteins. At their N-terminus, each has a C2 domain, which plays a role in proper cellular localization. The central portion of each protein contains two-to-four WW domains, which are responsible for target recognition. WW domains are 20–23 amino acid, Trp-based motifs that recognize PY motifs (PPXY, LPXY), as well as some phospho-Ser- or phospho-Thr-based motifs. At the C-terminus is the HECT domain, which directly conjugates an ubiquityl moiety to the target protein. The family members are grouped together by name and homology. ITCH is more closely homologous to WWP1 and 2 than to other family members.</p

Expression levels of the NEDD4 family in CRC.

<p>(A) The expression of all nine NEDD4 family members was examined in CRC by microarray profiling. Shown here is the average fold-change of all probes for each individual gene in Nl (N = 10), Ad (N = 6), Ca1 (N = 33), Ca2 (N = 76), Ca3 (N = 82), and Ca4 (N = 59). (B) <i>NEDD4</i> (213012_at) is the most highly upregulated member of the NEDD4 family in CRC. (C) <i>NEDD4L</i> (212445_s_at) is the most highly downregulated member of the NEDD4 family in CRC. Nl =  normal, Ad =  adenoma, and Ca1-4 = CRC, stage I-IV. *p<0.05.</p

The known targets of the NEDD4 family, the signaling pathways affected, and their expression levels in human cancers.

<p>In the “Signaling pathways affected” and “Expression in cancer” columns, ↓ indicates inhibition and downregulation, respectively, while ↑ indicates activation and upregulation. Patched (PTC), epithelial sodium channel (ENaC), cyclic nucleotide ras GEF (CNrasGEF), androgen receptor (AR), B-cell CLL/lymphoma 10 (Bcl10), potassium voltage-gated channel, shaker-related subfamily, member 3 (Kv1.3), sodium/glucose cotransporter 1 (SGLT1), sodium channel, voltage-gated, type V (NaV1.5), amyloid beta A4 precursor protein-binding family B member 1 (Fe65), dopamine transporter (DAT), inhibitor of growth 2 (ING2).</p

NEDD4L inhibits canonical WNT signaling at or below the level of β-catenin activation.

<p>(A) NEDD4L inhibits TOPFlash activity in HEK293 cells compared to empty vector (CTL) or catalytically inactive NEDD4L [NEDD4L (C>A)]. WNT3A (20 ng/ml) and R-spondin (100 ng/ml) were used to activate canonical WNT signaling. (B) When two different β-catenin constructs, β-catenin (wt) and β-catenin (ΔN89), are used to activate canonical WNT signaling a significant reduction in TOPFlash activity was observed in the presence of NEDD4L overexpression, as compared to empty vector or NEDD4L (C>A). All results are normalized to FOPFlash activity. *p<0.05.</p

Natural language processing for abstraction of cancer treatment toxicities: accuracy versus human experts.

ObjectivesExpert abstraction of acute toxicities is critical in oncology research but is labor-intensive and variable. We assessed the accuracy of a natural language processing (NLP) pipeline to extract symptoms from clinical notes compared to physicians.Materials and methodsTwo independent reviewers identified present and negated National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE) v5.0 symptoms from 100 randomly selected notes for on-treatment visits during radiation therapy with adjudication by a third reviewer. A NLP pipeline based on Apache clinical Text Analysis Knowledge Extraction System was developed and used to extract CTCAE terms. Accuracy was assessed by precision, recall, and F1.ResultsThe NLP pipeline demonstrated high accuracy for common physician-abstracted symptoms, such as radiation dermatitis (F1 0.88), fatigue (0.85), and nausea (0.88). NLP had poor sensitivity for negated symptoms.ConclusionNLP accurately detects a subset of documented present CTCAE symptoms, though is limited for negated symptoms. It may facilitate strategies to more consistently identify toxicities during cancer therapy

NEDD4L Is Downregulated in Colorectal Cancer and Inhibits Canonical WNT Signaling

The NEDD4 family of E3 ubiquitin ligases includes nine members. Each is a modular protein, containing an N-terminal C2 domain for cell localization, two-to-four central WW domains for substrate recognition, and a C-terminal, catalytic HECT domain, which is responsible for catalyzing the ubiquitylation reaction. Members of this family are known to affect pathways central to the pathogenesis of colorectal cancer, including the WNT, TGFβ, EGFR, and p53 pathways. Recently, NEDD4 mRNA was reported to be overexpressed in colorectal cancer, but tumor stage was not considered in the analysis. Expression of the other family members has not been studied in colorectal cancer. Herein, we determined the expression patterns of all nine NEDD4 family members in 256 patients who presented with disease ranging from premalignant adenoma to stage IV colorectal cancer. NEDD4 mRNA was significantly increased in all stages of colorectal cancer. In contrast, NEDD4L mRNA, the closest homolog to NEDD4, was the most highly downregulated family member, and was significantly downregulated in all tumor stages. We also found NEDD4L protein was significantly decreased by western blotting in colorectal cancer samples compared to adjacent normal mucosa. In addition, NEDD4L, but not catalytically inactive NEDD4L, inhibited canonical WNT signaling at or below the level of β-catenin in vitro. These findings suggest that NEDD4L may play a tumor suppressive role in colorectal cancer, possibly through inhibition of canonical WNT signaling