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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]

Parathyroidectomy is the standard management for patients with tertiary hyperparathyroidism (THPT) and hypercalcemia. However, a subset of patients with THPT have normal or mildly-elevated serum calcium levels in the setting of significantly elevated parathyroid hormone (PTH). The purpose of this study is to determine the effectiveness and safety of parathyroidectomy in normocalcemic THPT. Retrospective review of 212 consecutive patients with THPT who subsequently underwent parathyroidectomy between 2001 and 2020 was performed. Patients were categorized as normocalcemic, "mild" (Ca ≤ 10.4 mg/dL) or hypercalcemic, "classic" THPT (Ca ≥ 10.5 mg/dL) and clinical data are compared. 71 of 212 (34%) were normocalcemic with median pre-operative Ca and PTH levels of 9.7 mg/dL and 225pg/mL, respectively and 141 of 212 (67%) were hypercalcemic with median preoperative Ca and PTH levels of 11 mg/dL and 211pg/mL, respectively. The mean length of stay was shorter in normocalcemic patients (0.33 versus 0.50 d; P = 0.03). 10 of 71 (14%) normocalcemic patients underwent reoperative parathyroidectomy, more than double that of hypercalcemic patients (5.6%; P = 0.06). Concomitant thymectomy was performed in 28.1% and 22.1% of normocalcemia and hypercalcemic patients, respectively (P = 0.44). No patient in either group required intravenous calcium or had undetectable PTH levels, but permanent hypocalcemia was more frequent in normocalcemic compared to hypercalcemic patients (11.2% versus 1.4%; P = 0.03). Parathyroidectomy for normocalcemic tertiary hyperthyroidism (HPT) can be performed safely. These data can help guide multidisciplinary discussions for earlier surgical referral and intervention. Future investigations are needed to evaluate the impact of parathyroidectomy on the renal allograft, bone health, and cardiovascular disease. [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]

Insulinomas are rare endocrine malignancies of the pancreas that require surgical resection but can be difficult to localize preoperatively. We sought to review and improve the accuracy of preoperative localization techniques at our institution. We retrospectively reviewed all insulinomas that underwent resection at our institution between 1998 and 2016. Localization techniques include selective arterial calcium stimulation (CaStim), CT, MRI, angiography, and somatostatin receptor scintigraphy. Thirty-eight patients had pathologically proven insulinomas on surgical resection. Localization accuracies of CaStim, CT, and MRI were 89 per cent (31/35), 67 per cent (22/33), and 46 per cent (11/24), respectively. When compared with CT alone and CaStim alone, the combination of these two modalities resulted in 100 per cent preoperative localization (30/30), whereas the use of CaStim alone resulted in 80 per cent (4/5) localization and the use of CT alone resulted in 66 per cent (2/3) localization. Four of our patients had both negative CT and MRI. Among these patients, CaStim was 100 per cent localizing and the only positive modality for these patients. These data confirm that CaStim is accurate in preoperatively identifying single and multiple insulinomas; and when combined with CT, this accuracy is increased to 100 per cent. Based on these data, we propose that a dual imaging approach is a superior means of preoperative localization. [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]

Postoperative acute renal failure is a major cause of morbidity and mortality in colon and rectal surgery. Our objective was to identify preoperative risk factors that predispose patients to postoperative renal failure and renal insufficiency, and subsequently develop a risk calculator. Using the National Surgical Quality Improvement Program Participant Use Files database, all patients who underwent colorectal surgery in 2009 were selected (n = 21,720). We identified renal complications during the 30-day period after surgery. Using multivariate logistic regression analysis, a predictive model was developed. The overall incidence of renal complications among colorectal surgery patients was 1.6 per cent. Significant predictors include male gender (adjusted odds ratio [OR]: 1.8), dependent functional status (OR: 1.5), preoperative dyspnea (OR: 1.5), hypertension (OR: 1.6), preoperative acute renal failure (OR: 2.0), American Society of Anesthesiologists class ≥3 (OR: 2.2), preoperative creatinine >1.2 mg/dL (OR: 2.8), albumin <3.5 g/dL (OR: 1.8), and emergency operation (OR: 1.5). This final model has an area under the curve (AUC) of 0.79 and was validated with similar excellent discrimination (area under the curve: 0.76). Using this model, a risk calculator was developed with excellent predictive ability for postoperative renal complications in colorectal patients and can be used to aid clinical decision-making, patient counseling, and further research on measures to improve patient care. [ABSTRACT FROM AUTHOR]

Background: Attempts at preoperative localization of abnormal parathyroid gland(s) in primary hyperparathyroidism (pHPT) can be performed with a variety of modalities. Study utilization is surgeon-specific with highly variable opinions in parathyroid surgery. As more people are diagnosed with pHPT, the complexity of the disease has given rise to variation in management. This heterogeneity raises the question of the true clinical practice of imaging among individual endocrine surgeons. Methods: To better understand the preoperative parathyroid imaging practices of endocrine surgeons, an email-based survey was disseminated to the program directors of 22 American Association of Endocrine Surgeons fellowship programs querying them on their initial diagnostic test of choice for pHPT. Clinical support team members from each respective program were subsequently contacted and answers were compared. Results: Sixty-eight percent (15/22) of clinical team members recommended either an additional (12/15) or different imaging test (3/15) than what was recommended by their institution's endocrine surgeon. The most common initial imaging test that was repeated by both the endocrine surgeon and clinical team member was neck ultrasound; 33% of clinical team members (7/22) responded concordantly to their surgeon with ultrasound as the initial recommendation. Discussion: Significant variability exists in the preoperative approach to patients with hyperparathyroidism. Here, we demonstrate that inconsistency in preoperative imaging recommendations even extends to within an individual surgeon's practice based on the impact of the clinical support team, highlighting the role for improved clinical protocols within an institution's clinical team. [ABSTRACT FROM AUTHOR]

• Central neck dissection in cN0 PTC does not show oncologic benefit. • Central neck dissection in cN0 PTC associated with postoperative morbidity. • Central neck dissection in cN0 PTC should not be routinely performed. Central neck dissection (CND) remains a controversial intervention for papillary thyroid carcinoma (PTC) patients with clinically negative nodes (cN0) in the central compartment. Proponents state that CND in cN0 patients prevents locoregional recurrence, while opponents deem that the risks of complications outweigh any potential benefit. Thus, there remains conflicting results amongst studies assessing oncologic and surgical outcomes in cN0 PTC patients who undergo CND. To provide clarity to this controversy, we sought to evaluate the efficacy, safety, and oncologic impact of CND in cN0 PTC patients at our institution. Six hundred and ninety-five patients with PTC who underwent thyroidectomy at our institution between 1998 and 2018 were identified using an institutional cancer registry and supplemental electronic medical record queries. Patients were stratified by whether or not they underwent CND; identified as CND(+) or CND(-), respectively. Patients were also stratified by whether or not they received adjuvant radioactive iodine (RAI) therapy. Patient demographics, pathologic results, as well as surgical and oncologic outcomes were reviewed. Standard statistical analyses were performed using ANOVA and/or t -test and chi-squared tests as appropriate. Among the 695 patients with PTC, 492 (70.8%) had clinically and radiographically node negative disease (cN0). The mean age was 50 ± 1 years old and 368 (74.8%) were female. Of those with cN0 PTC, 61 patients (12.4%) underwent CND. CND(+) patients were found to have higher preoperative thyroid stimulating hormone (TSH) values, 2.8 ± 0.8 versus 1.5 ± 0.2 mU/L (P = 0.028) compared to CND(-) patients. CND did not significantly decrease disease recurrence, development of distant metastatic disease (P = 0.105) or persistence of disease (P = 0.069) at time of mean follow-up of 38 ± 3 months compared to CND(-) patients. However, surgical morbidity rates were significantly higher in CND(+) patients; including transient hypocalcemia (36.1% versus 14.4%; P < 0.001), transient recurrent laryngeal nerve (RLN) injury (19.7% vers us 7.0%; P < 0.001), and permanent RLN injury (3.3% versus 0.7%; P < 0.001). The majority of patients at our institution with cN0 PTC did not undergo CND. This data suggests that CND was not associated with improvements in oncologic outcomes during the short-term follow-up period and led to increased postoperative morbidity. Therefore, we conclude that CND should not be routinely performed for patients with cN0 PTC. [ABSTRACT FROM AUTHOR]

Background: The threshold at which active surveillance can be considered is variable, with some algorithms proposing nonoperative treatment for differentiated thyroid carcinomas ≤2 cm and lobectomy alone for lesions 2.1-4 cm. To inform both decision for and extent of initial surgery, we aim to evaluate whether molecular results can complement tumor size to identify differentiated thyroid carcinomas associated with disease recurrence., Methods: Patients from 2007-2013 and 2017-2021 who had initial thyroidectomy (differentiated thyroid carcinoma size 1-4 cm, clinical N0M0) were included. When available, molecular testing results were categorized into 3 previously described molecular risk groups (low, intermediate, and high). Primary outcome was structural recurrence., Results: Recurrence was diagnosed in 3.8% of 1,739 patients with differentiated thyroid carcinomas. Preoperative variables including size (1-2 cm vs 2.1-4 cm, P = .43), age >55 years (P = .92), and male sex (P = .31) were not associated with recurrence. Molecular testing results were available for 1,020, and after excluding molecular risk group high-risk differentiated thyroid carcinoma, structural recurrences were associated with molecular risk group intermediate risk (7.2% vs molecular risk group low, 0.7%, P < .001), and most likely in differentiated thyroid carcinoma, which were both 2.1-4 cm and molecular risk group intermediate risk (11.3% vs size 1-2 cm 5.8%, P = .04)., Conclusion: Overall, structural recurrences for differentiated thyroid carcinomas ≤4 cm were low (<5%) and molecuar testing was the only preoperative variable associated with recurrence. However, when molecular risk group intermediate risk was present, larger tumor size (2.1-4 cm) had a 2-fold greater risk of recurrence compared with tumors 1-2 cm, and size may still be helpful to guide management. When considering de-escalated treatment for the proposed guidelines with a cutoff of 2 cm, initial decision-making may be further optimized with identification of preoperative molecular risk groups., Competing Interests: Conflict of Interest/Disclosure Yuri E. Nikiforov and Marina N. Nikiforova own intellectual property for ThyroSeq, receive royalties from the University of Pittsburgh, and are also consultants for Sonic Healthcare USA. The remaining authors have no conflicts of interest or disclosures., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Objective: To determine whether the timing of parathyroid surgery impacts the risk of renal stone retreatment and cardiovascular interventions., Summary Background Data: Long-term, untreated primary hyperparathyroidism is associated with significant morbidity including nephrolithiasis and cardiovascular disease., Methods: We conducted a Population-based Cohort study of New York and California state-wide data from 2000-2020. Adult patients who underwent renal stone treatment and subsequently diagnosed with primary hyperparathyroidism (pHPT) and underwent parathyroidectomy (PTX) were included. Patients were excluded if PTX was prior to index stone procedure, they underwent second stone treatment within 6 months, with stage V CKD, with secondary or tertiary hyperparathyroidism, with prior kidney transplant or hemodialysis, or with prior cancer diagnosis. Rate of renal stone retreatment and cardiovascular interventions after PTX in pHPT patients with nephrolithiasis who underwent parathyroid surgery at ≤ 2 years and >2 years after index stone procedure was measured., Results: We identified 2,093 patients who underwent first-time stone treatment and subsequent PTX. The median time to PTX was 560 days (IQR 187-1477) and follow-up was 7.4 years (IQR 4.5-13.1). Delaying PTX for more than 2 years increased the risk of renal stone retreatment by 59% (HR 1.59; P<0.001), increased the risk of experiencing coronary disease or associated interventions by 118% (HR=2.18; P=0.01), and increased the risk of experiencing an overall cardiovascular event by 52% (HR 1.52; P<0.01)., Conclusions and Relevance: In symptomatic pHPT, delaying PTX significantly increases the risk of requiring future stone retreatment and cardiac/vascular surgical interventions. This highlights the importance of early surgical referral and multidisciplinary approaches to optimize outcomes and resource utilization in pHPT., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Normocalcemic primary hyperparathyroidism (PHPT) has been shown to benefit from parathyroidectomy. PHPT may be localized preoperatively with various imaging modalities, but the utility of preoperative imaging in normocalcemic PHPT compared to hypercalcemic PHPT is not well defined., Methods: Retrospective review was performed on all PHPT patients who underwent parathyroidectomy from 2001 to 2019. Patients were stratified into normocalcemic and hypercalcemic groups. Patient and outcomes data were analyzed., Results: All 2218 patients in this database were included. 433 patients had normocalcemic PHPT (19.5%) and 1785 had hypercalcemic PHPT (80.5%). Among normocalcemic patients, equivalent cure rates were seen between patients with preoperative imaging versus those without (100% vs 99%). No differences in postoperative complications were demonstrated except for a slightly increase in transient hypocalcemia in patients without imaging., Conclusions: Normocalcemic PHPT patients had equivalent cure and similar complication rates with or without preoperative imaging compared to hypercalcemic patients. Routine localization studies in normocalcemic PHPT may be safely omitted in favor of exploration with intraoperative adjuncts by experienced surgeons., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Expression of the tight junction-associated protein junctional adhesion molecule-A (JAM-A) is increased in sepsis, although the significance of this is unknown. Here, we show that septic JAM-A -/- mice have increased gut permeability, yet paradoxically have decreased bacteremia and systemic TNF and IL-1β expression. Survival is improved in JAM-A-/- mice. However, intestine-specific JAM-A-/- deletion does not alter mortality, suggesting that the mortality benefit conferred in mice lacking JAM-A is independent of the intestine. Septic JAM-A-/- mice have increased numbers of splenic CD44hiCD4+ T cells, decreased frequency of TNF+CD4+ cells, and elevated frequency of IL-2+CD4+ cells. Septic JAM-A-/- mice have increased numbers of B cells in mesenteric lymph nodes with elevated serum IgA and intraepithelial lymphocyte IgA production. JAM-A-/- × RAG-/- mice have improved survival compared with RAG-/- mice and identical mortality as WT mice. Gut neutrophil infiltration and neutrophil phagocytosis are increased in JAM-A-/- mice, while septic JAM-A-/- mice depleted of neutrophils lose their survival advantage. Therefore, increased bacterial clearance via neutrophils and an altered systemic inflammatory response with increased opsonizing IgA produced through the adaptive immune system results in improved survival in septic JAM-A-/- mice. JAM-A may be a therapeutic target in sepsis via immune mechanisms not related to its role in permeability.

Background: Hypoparathyroidism is the most common complication of bilateral operations in the central neck. No formal guidelines exist for the management of permanent hypoparathyroidism. Current treatment involving medical supplementation increases resource utilization and patient morbidity while decreasing quality of life. Parathyroid allotransplant (PA) offers a promising therapy; however, the optimal technique and role of immunosuppression (IS) in PA remain unclear., Methods: We performed a systematic search of the Embase, MEDLINE, and Cochrane Library databases to identify studies investigating PA for treatment of hypoparathyroidism., Results: A total of 24 studies including 186 individual allograft transplants in 146 patients were identified. Pooled graft survival for allotransplants in transplant-naïve vs prior transplant recipients was 29.9% and 80%, respectively., Conclusions: PA using normocellular, fresh parathyroid donor tissue that is ABO-compatible, with induction and, at minimum, short-term maintenance IS presents a potentially safe and effective therapeutic option for permanent hypoparathyroidism in patients tolerating IS., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Background: The majority of ectopic mediastinal parathyroid adenomas are accessible transcervically and those not amenable to this approach pose a significant clinical and technical challenge., Methods: Retrospective review of transthoracic robot-assisted mediastinal parathyroidectomy (TTRMP) for primary hyperparathyroidism between 2012 and 2019 at a single institution., Results: 16 patients underwent TTRMP, 63% were female with a mean age of 64 ± 2.0 years. Nine of 16 had prior parathyroidectomy; 80% had persistent disease and a mean 2.8-year delay from index operation until TTRMP. Locations included: intrathymic (8), AP window (4), carina (3), and retroesophageal (1). Two patients underwent parathyroid reimplantation. Mean post-operative calcium and PTH were 9.2 ± 0.2 mg/dL and 20.2 ± 5.6 pg/mL, respectively. Complications included: temporary hypocalcemia (4), permanent hypocalcemia (1), DVT (1), hoarseness (1), and subcostal neuralgia (1)., Conclusion: In experienced hands, TTRMP is a safe and effective approach to mediastinal parathyroids not accessible transcervically. A multidisciplinary approach should be used in reoperative cases., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Introduction: Papillary thyroid cancer (PTC) is the most common form of thyroid cancer. Although the survival rate is excellent, recurrence is as high as 20%. The mainstay of therapy is thyroidectomy and lymph node dissection based on risk factors. Data from other cancers suggest that surgical outcomes are most optimal at comprehensive cancer centers. We hypothesize that patients with PTC who had their initial operation at a comprehensive cancer center would have a better oncologic outcome., Methods: We utilized an IRB-approved cancer care registry database of patients with thyroid cancer who were seen at our institution between 2000 and 2018. Patient records were updated with cancer-specific outcomes including recurrence and need for re-intervention. Clinical and surgical outcomes were then compared between patients who had their initial operation at a comprehensive cancer center (CCC group, n = 503) versus those who did not (non-CCC group, n = 72)., Results: Mean patient age was 49 ± 16 years and 70% were female. Average tumor size was 1.6 ± 1.6 cm. There was no difference in tumor size, age, gender or race between groups. Pre-operative ultrasound was more frequently performed at the CCC (89%) than at non-CCC's (51%, p < 0.001). CCC patients were more likely to undergo initial total thyroidectomies compared to non-CCC patients (76% vs. 21%, p < 0.001). Positive surgical margins were more frequently found in patients at non-CCC's (19%) than at the CCC (9.7%, p = 0.016). Finally, CCC patients had a significantly lower cancer recurrence rate (5.0% vs. 37.5%, p < 0.001). Therefore, the need for additional cancer operations was much greater in patients who had initial thyroid surgery at non-CCC (31.9% vs. 1.4%, p < 0.001)., Conclusions: Patients with PTC who have their initial thyroidectomy at non-CCC have higher recurrence rates, higher rates of positive tumor margins on pathology, and increased need for additional operations. These data suggest that patients who have their initial procedure at a CCC for PTC have better long-term outcomes., Competing Interests: Declaration of competing interest The authors report no proprietary or commercial interest in any product mentioned or concept discussed in this article., (Copyright © 2021 Elsevier Inc. All rights reserved.)

TIGIT is a recently identified coinhibitory receptor that is upregulated in the setting of cancer and functionally contributes to the impairment of antitumor immunity. However, its role during sepsis is unknown. Because patients with cancer are 10 times more likely to die of sepsis than previously healthy (PH) patients with sepsis, we interrogated the role of TIGIT during sepsis in the context of preexistent malignancy. PH mice or cancer (CA) mice inoculated with lung carcinoma cells were made septic by cecal ligation and puncture (CLP). We found that sepsis induced TIGIT upregulation predominantly on Tregs and NK cells in both PH and CA mice. Anti-TIGIT Ab improved the 7-d survival of CA septic mice but not PH mice after CLP. Treatment of CA septic animals but not PH septic animals with anti-TIGIT mAb significantly reversed sepsis-induced loss of CD4+ T cells, CD8+ T cells, Foxp3+ Treg, and CD19+ B cells in the spleen, which was the result of decreased caspase-3+ apoptotic cells. In sum, we found that anti-TIGIT Ab reversed sepsis-induced T cell apoptosis in CA septic mice and led to a significant survival benefit, suggesting its use as a potential immunotherapy to improve outcomes in septic patients with cancer.

Background: Re-operative parathyroidectomy in patients with recurrent or persistent hyperparathyroidism can be challenging. We review our experience to determine the optimal number of localization studies prior to re-operation., Methods: From 2001 to 2019, 251 patients underwent re-operative parathyroidectomy. Parathyroidectomies were stratified to 4 groups based upon the number of positive localization studies obtained: A) ZERO, B) 1-positive, C) 2-positive, D) 3-positive., Results: The overall cure rate was 97%, where 201 single gland resections, 23 two-gland resections, 22 subtotal/total, and 5 forearm autograft resections were performed. Thirty-two patients had no positive studies (A), 172 patients had 1-positive (B), 42 patients had 2-positive (C), and 5 patients had 3-positive studies (D). There was no difference in surgical cure rates between groups (p = 0.71). The majority of patients had one or no positive imaging studies yet almost all still achieved cure., Conclusion: Successful re-operative parathyroidectomy can be performed with minimal pre-operative scans in certain clinical contexts., Competing Interests: Declaration of competing interest The authors have no conflicts of interest to disclose., (Copyright © 2020 Elsevier Inc. All rights reserved.)

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.

CD8 T cell loss and dysfunction have been implicated in the increased susceptibility to opportunistic infections during the later immunosuppressive phase of sepsis, but CD8 T cell activation and attrition in early sepsis remain incompletely understood. With the use of a CLP model, we assessed CD8 T cell activation at 5 consecutive time points and found that activation after sepsis results in a distinct phenotype (CD69 + CD25 int CD62L HI ) independent of cognate antigen recognition and TCR engagement and likely through bystander-mediated cytokine effects. Additionally, we observed that sepsis concurrently results in the preferential depletion of a subset of memory-phenotype CD8 T cells that remain "unactivated" (i.e., fail to up-regulate activation markers) by apoptosis. Unactivated CD44 HI OT-I cells were spared from sepsis-induced attrition, as were memory-phenotype CD8 T cells of mice treated with anti-LFA-1 mAb, 1 h after CLP. Perhaps most importantly, we demonstrate that attrition of memory phenotype cells may have a pathologic significance, as elevated IL-6 levels were associated with decreased numbers of memory-phenotype CD8 T cells in septic mice, and preservation of this subset after administration of anti-LFA-1 mAb conferred improved survival at 7 d. Taken together, these data identify potentially modifiable responses of memory-phenotype CD8 T cells in early sepsis and may be particularly important in the application of immunomodulatory therapies in sepsis., (© Society for Leukocyte Biology.)