Staging information is essential for colorectal cancer research. Medicare claims are an important source of population-level data but currently lack oncologic stage. We aimed to develop a ...claims-based model to identify stage at diagnosis in patients with colorectal cancer.
We included patients age 66 years or older with colorectal cancer in the SEER-Medicare registry. Using patients diagnosed from 2014 to 2016, we developed models (multinomial logistic regression, elastic net regression, and random forest) to classify patients into stage I-II, III, or IV on the basis of demographics, diagnoses, and treatment utilization identified in Medicare claims. Models developed in a training cohort (2014-2016) were applied to a testing cohort (2017), and performance was evaluated using cancer stage listed in the SEER registry as the reference standard.
The cohort of patients with 30,543 colorectal cancer included 14,935 (48.9%) patients with stage I-II, 9,203 (30.1%) with stage III, and 6,405 (21%) with stage IV disease. A claims-based model using elastic net regression had a scaled Brier score (SBS) of 0.45 (95% CI, 0.43 to 0.46). Performance was strongest for classifying stage IV (SBS, 0.62; 95% CI, 0.59 to 0.64; sensitivity, 93%; 95% CI, 91 to 94) followed by stage I-II (SBS, 0.45; 95% CI, 0.44 to 0.47; sensitivity, 86%; 95% CI, 85 to 76) and stage III (SBS, 0.32; 95% CI, 0.30 to 0.33; sensitivity, 62%; 95% CI, 61 to 64).
Machine learning models effectively classified colorectal cancer stage using Medicare claims. These models extend the ability of claims-based research to risk-adjust and stratify by stage.
BRAF
is the most common mutation in papillary thyroid carcinoma (PTC) and can be associated with aggressive disease. Previously, a highly sensitive blood RNA-based BRAF
assay was reported. The ...objective of this study was to assess the correlation of BRAF
circulating tumor RNA levels with surgical and medical treatment.
Circulating BRAF
levels were assessed in (i) a murine model of undifferentiated (anaplastic) thyroid carcinoma with known BRAF
mutation undergoing BRAF
-inhibitor (BRAFi) treatment, and (ii) in 111 patients enrolled prior to thyroidectomy (n = 86) or treatment of advanced recurrent or metastatic PTC (n = 25). Blood samples were drawn for BRAF
analysis before and after treatment. Testing characteristics were assessed and positivity criteria optimized. Changes in blood BRAF
values were assessed and compared to clinical characteristics and response to therapy.
In a murine model of anaplastic thyroid carcinoma with BRAF
mutation, blood BRAF
RNA correlated with tumor volume in animals treated with BRAFi. In tissue BRAF
-positive (n = 36) patients undergoing initial surgery for PTC, blood BRAF
levels declined postoperatively (median 370.0-178.5 fg/ng; p = 0.002). In four patients with metastatic or poorly differentiated thyroid carcinoma receiving targeted therapies, blood BRAF
declined following therapy and corresponded with radiographic evidence of partial response or stable disease.
This study shows the correlation of blood BRAF
levels in response to treatment in both an established animal model of thyroid cancer and in patients with BRAF
-positive tumors with all stages of disease. This assay represents an alternative biomarker in patients with positive thyroglobulin antibodies, and tumors, which do not express thyroglobulin.
Abstract
Context and Objectives
Urinary bladder paraganglioma (UBPGL) is rare. We aimed to characterize the presentation and outcomes of patients diagnosed with UBPGL.
Methods
We conducted a ...multi-center study of consecutive patients with pathologically-confirmed UBPGL evaluated between 1971 and 2021. Outcomes included repeat bladder surgery, metastases, and disease-specific mortality.
Results
110 patients (56, 51% women) were diagnosed with UBPGL at a median age of 50 years (IQR, 36-61 years). Median tumor size was 2 cm (IQR, 1-4 cm). UBPGL was diagnosed prior to biopsy in only 37 (34%), and only 69 (63%) patients had evaluation for catecholamine excess. In addition to the initial bladder surgery, 26 (25%) required multiple therapies, including repeat surgery in 10 (9%). Synchronous metastases were present in 9 (8%) patients, and 24 (22%) other patients with UBPGL developed metachronous metastases at a median of 4 years (IQR, 2-10 years) after initial diagnosis. Development of metachronous metastases was associated with younger age (Hazard ratio, HR 0.97, 95%CI 0.94-0.99), UBPGL size (HR of 1.69, 95%CI of 1.31-2.17), and a higher degree of catecholamine excess (HR of 5.48, 95%CI of 1.40-21.39). Disease-specific mortality was higher in patients with synchronous metastases (HR of 20.80, 95%CI, 1.30-332.91). Choice of initial surgery, genetic association, sex, or presence of muscular involvement on pathology were not associated with development of metastases or mortality.
Conclusions
Only a minority of patients were diagnosed before biopsy/surgery, reflecting the need of better diagnostic strategies. All patients with UBPGL should be monitored life-long for development of recurrence and metastases.
Presentation: Sunday, June 12, 2022 12:30 p.m. - 2:30 p.m., Monday, June 13, 2022 12:48 p.m. - 12:53 p.m.
Abstract
Background: Aldosterone-producing adenoma (APA) is a major subtype of primary aldosteronism (PA) which is the most common cause of endocrine-related hypertension. The Endocrine Society ...clinical practice guideline suggests that young patients (< 35 years old) with a CT-detected adrenocortical adenoma and typical phenotype of PA may not need adrenal venous sampling prior to adrenalectomy. In recent years, aldosterone-driver somatic mutations have been identified in APA, and prevalence studies suggest potential effects of patient age and sex. However, the rare nature of early-onset PA has prevented a detailed study of the histologic characteristics and aldosterone-driver somatic mutations in adrenal tumors from these patients.
Objective: To determine histologic and somatic mutation profile in early-onset APA.
Methods: Fifty-five formalin-fixed paraffin-embedded (FFPE) adrenals from patients at the age of 35 years old or younger who underwent adrenalectomy at the participating centers were studied (45 women, 9 men, and 1 unknown sex). CYP11B2 immunohistochemistry (IHC)-guided tumor capturing was used to selectively obtain DNA from APA. Mutation status was determined either by Sanger sequencing or targeted next-generation sequencing.
Results: CYP11B2 IHC identified APAs in all adrenal specimens. Solitary APAs were found in 53 adrenals. One adrenal had multiple APAs and one had a dominant CYP11B2-negative tumor and a smaller APA. In total, DNA from 57 APAs were sequenced. Two APAs were excluded from the analysis due to low sample quality. In 52 of the 55 APAs, somatic mutations were identified in one of the aldosterone-driver genes or CTNNB1 gene, encoding β-catenin. The most common genetic alteration was seen in KCNJ5 (37/55, 67%), followed by CACNA1D (7/55, 13%), ATP1A1 (3/55, 5%), CTNNB1 (3/55, 5%), and ATP2B3 (2/55, 4%). No sex difference in the prevalence of KCNJ5 mutation was observed in this age group.
Conclusion: The majority of adrenals from early-onset PA patients had a solitary APA. Regardless of sex, the most common genetic cause of early-onset APA was somatic mutations in KCNJ5.
T cell antigen recognition involves the formation of a structured interface between antigen-presenting and T cells that facilitates the specific transmission of activating and desensitizing stimuli. ...The molecular machinery that organizes the signaling molecules and controls their disposition in response to activation remains poorly understood. We show here that in T cells Discs large (Dlg1), a PDZ domain-containing protein, is recruited upon activation to cortical actin and forms complexes with early participants in T cell activation. Transient overexpression of Dlg1 attenuates basal and Vav1-induced NFAT reporter activation. Reduction of Dlg1 expression by RNA interference enhances both CD3- and superantigen-mediated NFAT activation. Attenuation of antigen receptor signaling appears to be a complex, highly orchestrated event that involves the mutual segregation of important elements of the early signaling complex.
Thyroid, Parathyroid, and Adrenal Glands FRAKER, DOUGLAS; WACHTEL, HEATHER
The Surgical Review : An Integrated Basic and Clinical Science Study Guide,
2016
Reference
IntroductionThe application of computational methods to electronic health record (EHR) data has the potential to dramatically improve population health by enabling systematic screening for ...underdiagnosed diseases. Primary aldosteronism (PA) is an excellent target for such approaches, because it is thought to affect ~1% of US adults but is diagnosed much less frequently. Thus, we sought to develop preliminary phenotyping models that leverage EHR data to identify unlabeled PA patients.MethodsWe studied 97,584 patients who received longitudinal primary care at our institution and had ≥2 hypertension diagnosis codes. We identified 454 PA patients based on chart review or a history of adrenal vein sampling or adrenalectomy for PA and ~7-fold controls (3,055 random, 131 chart-review negative). We extracted demographics, laboratory results, diagnosis codes, vitals, medication prescriptions, and simple concepts from notes between 1997 and 2017 from our clinical data repository. Longitudinal measures were aggregated using summary statistics. We trained an expert-curated computable phenotype and logistic lasso regression and random forest models in 90% of subjects and validated them in the remaining 10%.ResultsThe hand-crafted computable phenotype demonstrated a sensitivity of 0.79 and positive predictive value (PPV) of 0.85 in the validation set. The random forest model appeared to have the best discriminative performance, demonstrating a median sensitivity of 0.93 (IQR0.90 - 0.94) and PPV of 0.84 (0.84 - 0.85) in 5-fold cross-validation testing and a sensitivity of 0.98 and PPV of 0.87 in validation. The 10 model features with highest importance scores summarized blood aldosterone or renin, PA diagnosis codes, and counts of “hyperaldo” in notes. The application of this model to the full cohort predicted 260 (0.3%) positive patients. Chart review of the 20 patients with the highest prediction scores revealed 13 (65%) definitive and 3 (15%) possible PA patients.ConclusionWe developed a preliminary phenotyping model that uses retrospective EHR data to specifically identify unlabeled PA patients. This approach, with further refinements, will yield tools that could improve screening for PA and potentially other underdiagnosed diseases.
IntroductionPrimary aldosteronism (PA) is the most common cause of secondary hypertension, affecting 5% of hypertensive patients. The frequency of PA is enriched up to 20% in specific subgroups, ...including hypokalemic and resistant hypertension. AHA/ACC guidelines recommend screening these higher-risk patients for PA. Based on the observation of fewer PA patients in our clinical practice than predicted by epidemiological studies, we hypothesized that PA is underdiagnosed and that this deficit is in part due to insufficient screening.MethodsWe studied 243,820 patients receiving longitudinal primary care at our institution between 2007 and 2017. For these patients, we extracted diagnosis codes, laboratory results, medications, and vitals from our clinical data repository. We iteratively developed computable phenotypes to identify patients with hypertension, hypertension with unexplained hypokalemia, or resistant hypertension. Heuristics were trained by chart review of 700 random patients and 100 patients identified by preliminary heuristics and then validated in 300 random and 100 heuristic-flagged patients. PA patients were identified based on a history of a PA-specific clinical procedure or chart review.ResultsIn the validation set, the computable phenotypes demonstrated sensitivities of 0.94, 0.78, and 0.87 and PPVs of 0.98, 0.84, and 0.83 for hypertension, hypertension with unexplained hypokalemia, and resistant hypertension. We found that the prevalence of PA diagnoses in these cohorts were only 0.5% (N=442), 2.0% (N=321), and 1.5% (N=303), respectively. Similarly, the PA screening frequencies were only 3% (N=2,527), 7% (N=1,170) and 6% (N=1,280). Across 37 primary care practices, there was considerable variability in the PA diagnosis prevalence among hypertension patients (IQR= 0.14% - 0.63%) and this variability was strongly correlated with the frequency of PA screening (rho = 0.74; p = 1.7x10).ConclusionIn a large, diverse clinical practice, PA appears to be underdiagnosed and PA screening appears to be under-utilized relative to guidelines. The strong correlation between diagnosis and screening frequencies across practices suggests that interventions to improve screening may efficiently yield more diagnoses.
With the release of the 2015 management guidelines, the American Thyroid Association narrowed the indications for postoperative radioactive iodine (RAI) in well-differentiated thyroid cancer. ...However, the adoption of new guidelines varies between healthcare entities. The goal of this study was to characterize the appropriateness of RAI use within our health system, before and after the 2015 guideline changes.
In this retrospective cohort study, we identified patients who were treated for well-differentiated thyroid cancer between 2011–2020. Patients were characterized as “undertreated,” “appropriately treated,” or “overtreated” with RAI. Variation in RAI use was assessed using interrupted time series and multivariable logistic regression analyses.
Among 6310 patients, the mean age was 50 ± 15 years, and 74% were female. There was an immediate drop in the likelihood of receiving RAI after the release of the 2015 guidelines (p = 0.016), and the likelihood of receiving RAI therapy continued to significantly decline over time (OR 0.83, p < 0.001). Despite this trend in the absolute rate of RAI use, there was a significant increase in overtreatment with RAI after the release of the 2015 guidelines (p < 0.001), indicating imperfect uptake of the new criteria. Two hospitals within the health system were identified as disproportionate contributors to overtreatment (Hospital 4: OR 6.50, p < 0.001; Hospital 6: OR 8.63, p < 0.001).
While the use of postoperative RAI was largely appropriate across our health system, rates of guideline adherence differed between hospitals. Efforts to standardize treatment protocols systemwide may enable more rapid and consistent uptake of new management guidelines.
•Guidelines for radioactive iodine use in thyroid cancer changed in January 2016.•Rates of guideline adherence before and after these changes vary between hospitals.•Collaboration and standardization across health systems may improve care quality.
CARMA1 is a central regulator of NF- Kappa B activation in lymphocytes. CARMA1 and Bcl10 functionally interact and control NF- Kappa B signaling downstream of the T-cell receptor (TCR). Computational ...analysis of expression neighborhoods of CARMA1-Bcl10MALT 1 for enrichment in kinases identified calmodulin-dependent protein kinase II (CaMKII) as an important component of this pathway. Here we report that Ca super(2+)/CaMKII is redistributed to the immune synapse following T-cell activation and that CaMKII is critical for NF- Kappa B activation induced by TCR stimulation. Furthermore, CaMKII enhances CARMA1-induced NF- Kappa B activation. Moreover, we have shown that CaMKII phosphorylates CARMA1 on Ser109 and that the phosphorylation facilitates the interaction between CARMA1 and Bcl10. These results provide a novel function for CaMKII in TCR signaling and CARMA1-induced NF- Kappa B activation.
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