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Background: Indeterminate thyroid cytopathology diagnoses represent differing degrees of risk that are corroborated by follow‐up studies. However, traditional cytologic–histologic correlation may overestimate the risk of malignancy (ROM) because only a subset of cases undergo resection. Alternatively, some molecular tests provide probability of malignancy data to calculate the molecular‐derived risk of malignancy (MDROM) and the positive call rate (PCR). The authors investigated MDROMs and PCRs of indeterminate diagnoses for individual cytopathologists as quality metrics. Methods: This study was approved by the Department of Pathology Quality Improvement Program. Thyroid cytopathology diagnoses and ThyroSeq v3 results were retrieved for each cytopathologist for a 2‐year period with at least 3 years of follow‐up for the atypia of undetermined significance (AUS), follicular neoplasia (FN), and follicular neoplasia, oncocytic‐type (ONC) cytopathologic diagnoses. MDROMs and PCRs were compared with reference ROMs and cytologic–histologic correlation outcomes. Results: The overall MDROMs (and ranges for cytopathologists) for the AUS, FN, and ONC categories were 13.4% (range, 5.8%–20.8%), 28.1% (range, 22.1%–36.7%), and 27.0% (range, 19.5%–41.5%), respectively, and most individual cytopathologists' MDROMs were within reference ROM ranges. However, PCRs more effectively parsed the differences in cytopathologists' ROM performance. Although the overall PCRs were not significantly different across cytopathologists (p =.06), the AUS PCRs were quite different (p =.002). By cytologic–histologic correlation, six of 55 resected cases (10.9%) were falsely negative, and there were no false‐positive cases. Conclusions: MDROMs and PCRs evaluate concordance with reference ROMs and with one another and provide individual feedback, which potentially facilitates quality improvement. Cytopathologists' molecular‐derived risk of malignancy and positive call rates provide insights regarding their practice patterns when compared with reference ranges stated in the Bethesda System for Reporting Thyroid Cytopathology. This feedback is a useful tool from which systems improvement may be developed. [ABSTRACT FROM AUTHOR]

Background: Molecular testing (MT) is emerging as a potential prognostic factor that can be available before treatment of differentiated thyroid carcinoma begins. Among patients eligible for either lobectomy or total thyroidectomy as their initial therapy, our study aims were to assess (1) if conventionally available preoperative factors are associated with incomplete response to initial therapy, and (2) if MT results can be a surrogate for the ATA Risk Stratification System (RSS) to estimate risk of recurrence. Methods: The data of consecutive thyroid cancer patients without preoperative lateral neck disease or distant metastasis who underwent index thyroidectomy between November 1, 2017 and October 31, 2021 were reviewed. Logistic regression models including preoperative variables such as MT and/or the postoperatively available RSS were constructed to predict disease recurrence, either structural or biochemical. Model discrimination using the c-statistic and goodness-of-fit test were compared. Results: Among 945 patients studied, 50 (5.2%) recurred with 18-month median follow-up. Recurrences were detected in 17 (2.9%), 20 (6.7%), and 13 (22.8%) patients with RSS-low, -intermediate, and -high cancers, respectively (p < 0.001). In multivariable analysis, only tumor size was associated with recurrence (odds ratio [OR] 1.3, 95% confidence interval [CI] 1.1–1.5). In a different model analyzing 440 (46.6%) patients with available MT results, recurrence was associated with both larger tumor size (OR 1.4 [95% CI 1.1–1.8]) and MT results (p < 0.001). Including MT improved the c-statistic by 27%, which was statistically no different than the model incorporating only the RSS (p = 0.15). Conclusions: Disease recurrence was observed across all ATA RSS categories in short-term follow-up, and tumor size was the only conventional preoperative factor associated with recurrence. When MT results were incorporated, they not only improved predictive ability beyond tumor size alone, but also yielded similar ability as the gold standard ATA RSS. Thus, MT results might aid the development of novel preoperative risk stratification algorithms. [ABSTRACT FROM AUTHOR]

Background: Liver metastasis from duodenopancreatic neuroendocrine neoplasms (DP-NENs) is a major cause of mortality in multiple endocrine neoplasia type 1 (MEN1) patients, yet much of their natural history is unknown. Methods: This longitudinal, retrospective cohort study analyzed all MEN1 patients with imageable functional (F) and nonfunctional (NF) DP-NENs (1990–2021) for liver metastasis-free survival (LMFS) and overall survival (OS). Results: Of 138 patients, 85 (61.6%) had imageable DP-NENs (28 F, 57 NF), and the mean largest tumor size was 1.8 ± 1.4 cm. Multifocality was present in 32 patients (37.7%). Surgery was performed for 49 patients (57.7%). During an 11-year median follow-up period (IQR, 6–17 years), 23 (27.1%) of the patients had liver metastasis, and 19 (22.4%) patients died. Death was attributed to liver metastasis in 60% of cases. The patients with F-DP-NENs versus NF-DP-NENs more often had liver metastasis (46.4% vs. 15.8%; p = 0.002) but had similar 10-year LMFS (80.9 vs. 87.0%; p = 0.44) and OS (82.7 vs. 94.3%; p = 0.69). The patients with NF-DP-NENs had surgery when their tumors were larger (p < 0.001). Tumor size was not associated with liver metastasis (p = 0.89). The average growth rate was 0.04 cm/year (SE, 0.02 cm/year; p = 0.01) during active surveillance for NF-DP-NENs (n = 38). Liver metastasis developed in four patients with tumors smaller than 2 cm. The risk of liver metastasis was independent of surgery (hazard ratio [HR], 0.78; 95% confidence interval [CI], 0.21–2.93; p = 0.72) and death (HR, 0.51; 95% CI, 0.08–3.06; p = 0.46). Conclusions: Although the observed outcomes in this study were better than historical data, small NF-DP-NENs still developed liver metastasis and liver metastasis remains a major cause of death. These results suggest that size as a sole criterion for surgery may be insufficient to predict tumor behavior. [ABSTRACT FROM AUTHOR]

Patients with cancer are at an increased risk of developing and dying from sepsis. We previously reported that blockade of the chemokine receptor CXCR4 resulted in decreased CD4+ T cell exhaustion and improved survival in a model of polymicrobial sepsis in previously healthy mice. Here, we sought to determine whether CXCR4 blockade could improve mortality and immune dysregulation during sepsis complicated with malignancy. Results in animals inoculated with a lung cancer cell line and subjected to CLP 3 weeks later indicated that CXCR4 was up‐regulated on naïve and central memory T cells following sepsis. Of note, and in contrast to results in previously healthy mice, CXCR4 blockade failed to improve survival in cancer septic animals; instead, it actually significantly worsened survival. In the setting of cancer, CXCR4 blockade failed to result in T cell egress from the bone marrow, reverse lymphopenia in the spleen, or reverse T cell exhaustion. Mechanistically, elevated expression of CD69 on naïve T cells in the bone marrow of cancer septic animals was associated with their inability to egress from the bone marrow in the setting of CXCR4 blockade. In conclusion, these results illuminate the differential impact of CXCR4 blockade on sepsis pathophysiology in the setting of cancer and highlight the need for personalized therapy during sepsis. [ABSTRACT FROM AUTHOR]

Sepsis is a dysregulated systemic response to infection involving many inflammatory pathways and the induction of counter-regulatory anti-inflammatory processes that results in a state of immune incompetence and can lead to multi-organ failure. CXCR4 is a chemokine receptor that, following ligation by CXCL12, directs cells to bone marrow niches and also plays an important role in T cell cosignaling and formation of the immunological synapse. Here, we investigated the expression and function of CXCR4 in a murine model of polymicrobial sepsis. Results indicate that CXCR4 is selectively upregulated on naïve CD4+ and CD8+ T cells and CD4+ central memory T cells following the induction of sepsis, and that CXCR4 antagonism resulted in a significant decrease in sepsis-induced mortality. We probed the mechanistic basis for these findings and found that CXCR4 antagonism significantly increased the number of peripheral CD4+ and CD8+ T cells following sepsis. Moreover, mice treated with the CXCR4 antagonist contained fewer PD-1+ LAG-3+ 2B4+ cells, suggesting that blockade of CXCR4 mitigates CD4+ T cell exhaustion during sepsis. Taken together, these results characterize CXCR4 as an important pathway that modulates immune dysfunction and mortality following sepsis, which may hold promise as a target for future therapeutic intervention in septic patients. [ABSTRACT FROM AUTHOR]

[[4]] The authors appropriately highlight that the utilization of IOPTHM in parathyroid surgery for secondary and tertiary HPT is not intended to guide extent of initial dissection as these patients, in general, warrant four-gland exploration. Intraoperative parathyroid hormone monitoring (IOPTHM) is a well-studied and thoroughly validated adjunct to parathyroid surgery for primary hyperparathyroidism (HPT) [[1]]. [Extracted from the article]