Treatment Differences for Adrenocortical Carcinoma by Race and Insurance Status.

INTRODUCTION: To determine if treatment and clinical outcomes of adrenocortical carcinoma (ACC) vary by race and insurance status. METHODS: ACC patients from the National Cancer Database (2004-2017) were reviewed. Race was defined as White versus minority (Black and Hispanic). Insurance types were private (PI) versus other (Medicaid/uninsured/unknown). Metastatic ACC (M-ACC) was defined as distant metastases at the time of diagnosis; nonmetastatic ACC (NM-ACC) patient had no distant disease. RESULTS: Of 2351 NM-ACC patients, 83.6% were White and 16.4% minority. There were 1216 M-ACC patients, with 80.3% White and 19.8% minority. Both White NM-ACC and M-ACC patients had more PI (each P < 0.001). PI NM-ACC was associated with a shorter duration from diagnosis to first treatment (14 versus 18 d, P = 0.005). Both NM-ACC and M-ACC with PI were more likely to receive surgery (92.6% versus 86.9%, P = 0.001 and 35.4% versus 27%, P = 0.02) and to receive surgery sooner (13 versus 16 d, P = 0.03). M-ACC with PI were more likely to receive chemotherapy (63.6% versus 54.3%, P = 0.01) and to have lymph nodes examined (14.8% versus 8.6%, P = 0.02). Length of stay postoperatively was shorter for White NM-ACC (6 versus 7 d, P = 0.04) and M-ACC (8 versus 17 d, P = 0.02). For NM-ACC and M-ACC, the 30-d readmission, 90-d mortality, and overall survival were similar by race. A multivariable analysis showed minorities (OR 0.69, 95% confidence interval 0.54-0.88, P = 0.003) and patients without PI (OR 0.75, 95% confidence interval 0.58-0.97, P = 0.03) were less likely to have surgery. However, a multivariable analysis showed survival was similar for White versus minority patients and PI versus other. CONCLUSIONS: White NM-ACC or M-ACC and PI were more likely to receive surgery and timely multimodality care. These disparities were not associated with differences in 90-d mortality or overall survival.

A77 1726, the active metabolite of the anti-rheumatoid arthritis drug leflunomide, inhibits influenza A virus replication in vitro and in vivo by inhibiting the activity of Janus kinases.

The newly reassorted IAV subtypes from zoonotic reservoirs respond poorly to current vaccines and antiviral therapy. There is an unmet need in developing novel antiviral drugs for better control of IAV infection. The cellular factors that are crucial for virus replication have been sought as novel molecular targets for antiviral therapy. Recent studies have shown that Janus kinases (JAK), JAK1, and JAK2, play an important role in IAV replication. Leflunomide is an anti-inflammatory drug primarily used for treating rheumatoid arthritis (RA). Prior studies suggest that A77 1726, the active metabolite of leflunomide, inhibits the activity of JAK1 and JAK3. Our current study aims to determine if A77 1726 can function as a JAK inhibitor to control IAV infection. Here, we report that A77 1726 inhibited the replication of three IAV subtypes（H5N1, H1N1, H9N2）in three cell types (chicken embryonic fibroblasts, A549, and MDCK). A77 1726 inhibited JAK1, JAK2, and STAT3 tyrosine phosphorylation. Similar observations were made with Ruxolitinib (Rux), a JAK-specific inhibitor. JAK2 overexpression enhanced H5N1 virus replication and compromised the antiviral activity of A77 1726. Leflunomide inhibited virus replication in the lungs of IAV-infected mice, alleviated their body weight loss, and prolonged their survival. Our study demonstrates for the first time the ability of A77 1726 to inhibit JAK2 activity and suggests that inhibition of JAK activity contributes to its antiviral activity.

The Gli1-Snail axis contributes to Salmonella Typhimurium-induced disruption of intercellular junctions of intestinal epithelial cells.

Salmonella enterica serovar Typhimurium (S. Typhimurium) is a facultative intracellular pathogen that damages gastrointestinal tissue and causes severe diarrhoea. The mechanisms by which Salmonella disrupts epithelial barrier and increases the paracellular permeability are incompletely understood. Our present study aims to determine the role of Gli1, a transcription factor activated in the sonic hedgehog (Shh) pathway, in decreasing the levels of apical junction proteins in a Salmonella-infected human colonic epithelial cancer cell line, Caco-2, and in the intestinal tissue of Salmonella-infected mice. Here, we report that S. Typhimurium increased the mRNA and protein levels of Gli1 and Snail, a downstream transcription factor that plays an important role in the epithelial-to-mesenchymal transition (EMT). S. Typhimurium also decreased the levels of E-cadherin and three tight junction proteins (ZO-1, claudin-1, and occludin). Gli1 siRNA and GANT61, a Gli1-specific inhibitor, blocked S. Typhimurium-induced Snail expression, restored the levels of E-cadherin and tight junction proteins, and prevented S. Typhimurium-increased paracellular permeability. Further study showed that Gli1 was cross-activated by the MAP and PI-3 kinase pathways. S. Typhimurium devoid of sopB, an effector of the Type 3 secretion system (T3SS) responsible for AKT activation, was unable to induce Snail expression and to decrease the expression of apical junction proteins. Our study uncovered a novel role of Gli1 in mediating the Salmonella-induced disruption of the intestinal epithelial barrier.

Toll-like receptor signalling cross-activates the autophagic pathway to restrict Salmonella Typhimurium growth in macrophages.

It has been long recognised that activation of toll-like receptors (TLRs) induces autophagy to restrict intracellular bacterial growth. However, the mechanisms of TLR-induced autophagy are incompletely understood. Salmonella Typhimurium is an intracellular pathogen that causes food poisoning and gastroenteritis in humans. Whether TLR activation contributes to S. Typhimurium-induced autophagy has not been investigated. Here, we report that S. Typhimurium and TLRs shared a common pathway to induce autophagy in macrophages. We first showed that S. Typhimurium-induced autophagy in a RAW264.7 murine macrophage cell line was mediated by the AMP-activated protein kinase (AMPK) through activation of the TGF-ß-activated kinase (TAK1), a kinase activated by multiple TLRs. AMPK activation led to increased phosphorylation of Unc-51-like autophagy activating kinase (ULK1) at S317 and S555. ULK1 phosphorylation at these two sites in S. Typhimurium-infected macrophages overrode the inhibitory effect of mTOR on ULK1 activity due to mTOR-mediated ULK1 phosphorylation at S757. Lipopolysaccharide (LPS), flagellin, and CpG oligodeoxynucleotide, which activate TLR4, TLR5, and TLR9, respectively, increased TAK1 and AMPK phosphorylation and induced autophagy in RAW264.7 cells and in bone marrow-derived macrophages. However, LPS was unable to induce TAK1 and AMPK phosphorylation and autophagy in TLR4-deficient macrophages. TAK1 and AMPK-specific inhibitors blocked S. Typhimurium-induced autophagy and xenophagy and increased the bacterial growth in RAW264.7 cells. These observations collectively suggest that activation of the TAK1-AMPK axis through TLRs is essential for S. Typhimurium-induced autophagy and that TLR signalling cross-activates the autophagic pathway to clear intracellular bacteria.

Trends in nonoperative management of papillary thyroid microcarcinoma.

BACKGROUND: In 2010, a Japanese trial of nonoperative management for papillary thyroid microcarcinomas (PTmC) was published. This study determines if the prevalence of nonoperative management in the United States has changed and if there are predictors of this approach. METHODS: Patients treated for PTmC between 2004 and 2015 in the National Cancer Data Base were identified. Inclusion criteria were: classic or follicular variant papillary cancer histology, tumor size 1 to 10 mm, cN0 disease and no extrathyroidal extension or metastatic disease. Nonoperative management was assessed over time and compared between 2004-2010 and 2010-2015. Logistic regression identified factors associated with nonoperative management. RESULTS: Of 65 381 PTmC patients, 344 (0.5%) were treated nonoperatively. The annual rate of nonoperative management was similar at 0.6% in 2004 to 0.4% in 2010 (P = .755) but increased to 0.9% in 2015 (P < .001). There was no difference in patient age, race, comorbidities, or reason for nonoperative management between the two periods. Academic centers managed more patients nonoperatively. Multivariable logistic regression suggests older age, facility type, location, Hispanic, Asian, and Native American ethnicity were associated with nonoperative management. CONCLUSION: The vast majority of PTmC in the United States is treated with an operation. A small but significant increase in nonoperative management occurred between 2004-2010 and 2010-2015.

Parathyroidectomy is Safe in Elderly Patients: A National Surgical Quality Improvement Program Study.

BACKGROUND: With increasing age, the incidence of hyperparathyroidism is increased. This study evaluates parathyroidectomy outcomes in elderly patients. METHODS: Primary hyperparathyroidism patients having parathyroidectomy as listed in the 2005-2017 ACS-NSQIP database were separated by age: ≤60, 61-79 and ≥80. Outcomes included complications, 30-day mortality, return to the OR, operating times, and hospital length of stay (LOS). Multivariable logistic regression was used to compare patients 61-79 and ≥80 to those ≤60. Patients ≤60 and ≥80 were propensity score matched using gender, race, BMI, smoking status, steroid use, modified frailty index (mFI), ASA class, procedure, setting, anesthesia, and wound class. Morbidity and mortality were compared to ACS-NSQIP database patients having elective inguinal hernia repair. RESULTS: Of 47,701 patients: 22,220 were ≤60, 22,683 were 61-79, and 2798 were ≥80. Patients ≥80 had more complications (2.3% vs. 1.5% for 61-79 and 1.0% for ≤60, p < 0.01), LOS > 1 day (10.3% vs. 5.8% and 6.7%, p < 0.01), and mortality (0.21% vs. 0.11% and 0.03%, p < 0.01). On multivariable analysis of the overall population, older age, male gender, steroid use, high mFI, outpatient procedure, and general anesthesia increased the risk of complications. On propensity score matched analysis, there was no difference in complications (1.5% vs. 2.2%, p = 0.06) or mortality (0.04% vs. 0.23%, p = 0.12) between patients ≤60 and ≥80. Parathyroidectomy morbidity and mortality was lower than that for elective inguinal hernia repair in patients ≥80 (2.3% vs. 10% and 0.21% vs. 1.1%, p < 0.01). CONCLUSIONS: Parathyroidectomy is a safe operation, offering lower morbidity and mortality than elective hernia repair in all age groups including octogenarians.

Survival with Follicular and Hurthle Cell Microcarcinoma Compared to Papillary Thyroid Microcarcinoma: A Population Study of 84,532 Patients.

BACKGROUND: This study compares survival in patients with the rare subtypes of follicular (FTmC) and Hurthle cell (HCmC) microcarcinoma compared to that of papillary thyroid (PTmC) microcarcinoma. METHODS: Patients with FTmC and HCmC were selected from the National Cancer Database 2004-2015 and compared with PTmC. Patient clinicopathological characteristics and overall survival (OS) were analyzed. Multivariable logistic and Cox regression analysis evaluated binary outcomes and predictors of survival. A propensity score matched analysis using age, gender, race, extrathyroidal extension (ETE), nodal status, distant metastasis, radiation, and operation was performed to evaluate the difference in OS with FTmC, HCmC, and PTmC. RESULTS: We identified 858 FTmC, 476 HCmC, and 82,056 PTmC. FTmC was less likely to have macroscopic ETE compared to PTmC (2.6% vs. 3.1% p = 0.03), but more likely to have distant metastasis (2.3% vs. 0.2%, p < 0.01). FTmC and HCmC were less likely to have nodal metastasis (2.7%, 2.5% vs. 10.9%, p < 0.01). Ten-year OS was decreased in patients with FTmC (91.4%, p = 0.04) and HCmC (89.8%, p < 0.01) compared to PTmC (93.5%). On multivariable analysis, histology was not associated with OS. With HCmC, older age (OR 1.13, p < 0.01) and male gender (OR 2.72, p = 0.03) were associated with decreased OS. In propensity matched analysis, there was no difference in 10-year OS with FTmC and PTmC (91.4% vs. 93.7%, p = 0.54), but HCmC had decreased OS compared to PTmC (89.8% vs. 94.3%, p = 0.04). CONCLUSIONS: Patients with FTmC have comparable OS to those with PTmC, but HCmC has decreased OS especially in older and male patients.

Differences in the Impact of Age on Mortality in Well-Differentiated Thyroid Cancer.

INTRODUCTION: Well-differentiated thyroid cancer (WDTC) is unique in that patient age is part of staging. Several studies have shown a need to increase the age threshold in staging for WDTC, but the separate impact of age on prognosis for papillary and follicular carcinomas has not been examined. We hypothesize that age impacts survival differently for papillary and follicular carcinomas. METHODS: Patients with invasive papillary thyroid carcinoma (PTC) and follicular thyroid carcinoma (FTC) between 2004 and 2013 were identified in the National Cancer Database, and were stratified by histologic type. Overall survival (OS) was analyzed using multivariable Cox regression, and the Youden index was used to find the optimal age threshold for both histologies. RESULTS: A total of 204,139 patients with WDTC were identified. Ninety-two percent had PTC, while 7.7% had FTC. The average age was 48.4 years and OS was 96.3%, with a median follow-up of 52.7 months. When analyzing age in 5-year increments, 10-year mortality increased incrementally by 30-50% per age group for PTC, from age < 35 to ≥ 70 years, without an obvious inflection point. However, FTC patients experienced a more than threefold increase in 10-year mortality from age 40-44 years (2.5%) to age 45-49 years (7.9%). The same pattern was found on multivariable Cox regression. The Youden index found the optimal age thresholds were 58.5 years for PTC and 46.2 years for FTC. CONCLUSION: OS for PTC decreases incrementally with age, but OS for FTC decreases significantly in patients aged 45 years and older. A higher age threshold may inappropriately downstage some high-risk follicular cancer patients.

Minimally Invasive Adrenalectomy for Adrenocortical Carcinoma: Five-Year Trends and Predictors of Conversion.

BACKGROUND: Adrenocortical carcinoma (ACC) is rare but often fatal. Surgery offers the only chance of cure. As minimally invasive (MI) procedures for cancer become common, their role for ACC is still debated. We reviewed usage of MI approaches for ACC over time and risk factors for conversion using a large national database. METHODS: ACC patients with localized disease were identified in the National Cancer Data Base from 2010 to 2014. A retrospective review examined trends in the surgical approach over time. Patient demographics, surgical approach, and tumor characteristics between MI, open, and converted procedures were compared. RESULTS: 588 patients underwent adrenalectomy for ACC, of which 200 were minimally invasive. From 2010 to 2014, MI operations increased from 26 to 44% with robotic procedures increasing from 5 to 16%. The use of MI operations compared to open was not different based on facility type (p = 0.40) or location (p = 0.63). MI tumors were more likely to be confined to the adrenal (p < 0.001) but final margin status was not different (p = 0.56). Conversion was performed in 38/200 (19%). Average tumor size was 10.2 cm in the converted group compared to 8.6 cm in the MI group (p = 0.09). There was no difference in extent of disease (p = 0.33), margin status (p = 0.12), or lymphovascular invasion (p = 0.59) between MI and converted procedures. Tumor size > 5 cm was the only significant predictor of conversion (p = 0.04). No patients with pathologic stage I disease required conversion (0/19). CONCLUSIONS: The frequency of MI approaches for ACC is increasing. In the final year of the study, 44% of adrenalectomies were MI. Size > 5 cm was the only significant predictor of conversion.

CONCORDANCE OF PRE-OPERATIVE CLINICAL STAGE WITH PATHOLOGIC STAGE IN PATIENTS ≥45 YEARS OLD WITH WELL-DIFFERENTIATED THYROID CANCER.

OBJECTIVE: Clinical stage (cStage) in thyroid cancer determines extent of surgical therapy and completeness of resection. Pathologic stage (pStage) is an important determinant of outcome. The rate of discordance between clinical and pathologic stage in thyroid cancer is unknown. METHODS: The National Cancer Data Base was queried to identify 27,473 patients ≥45 years old with cStage I through IV differentiated thyroid cancer undergoing surgery from 2008-2012. RESULTS: There were 16,286 (59.3%) cStage I patients; 4,825 (17.6%) cStage II; 4,329 (15.8%) cStage III; and 2,013 (7.3%) cStage IV patients. The upstage rate was 15.1%, and the downstage rate was 4.6%. For cStage II, there was a 25.5% upstage rate. The change in cStage was a result of inaccurate T-category in 40.8%, N-category in 36.3%, and both in 22.9%. On multivariate analysis, the patients more likely to be upstaged had papillary histology, tumors 2.1 to 4 cm, total thyroidectomy, nodal surgery, positive margins, or multifocal disease. Upstaged patients received radioiodine more frequently (75.3% vs. 48.1%; P<.001). CONCLUSION: Approximately 20% of cStage is discordant to pStage. Certain populations are at risk for inaccurate staging, including cT2 and cN0 patients. Upstaged patients are more likely to receive radioactive iodine therapy. ABBREVIATIONS: CI = confidence interval; cStage = clinical stage; DTC = differentiated thyroid cancer; NCDB = National Cancer Data Base; OR = odds ratio; pStage = pathologic stage; RAI = radioactive iodine.

The extent of vascular resection is associated with perioperative outcome in patients undergoing pancreaticoduodenectomy.

BACKGROUND: Few studies have examined the relation between extent of vascular resection and morbidity following pancreaticoduodenectomy (PD) with vein resection (PDVR). METHODS: Patients undergoing PD for malignancy were identified using the American College of Surgeons National Surgical Quality Improvement Project from 2006 to 2013. Current procedural terminology codes were used to characterize PDVR. RESULTS: 9235 patients underwent PD, 977 (10.6%) had PDVR - 640 with direct and 224 with graft repair. PDVR had longer operative times (456 ± 136 vs 374 ± 128 min, p < 0.05) and higher intraoperative transfusions (1.8 ± 3.4 vs 4.3 ± 4.9 units, p < 0.05) than PD alone. On adjusted multivariable regression, PDVR with either direct or graft repairs was associated with higher rates of overall morbidity (OR [odds ratio] 1.50 for direct, 1.74 for graft, p < 0.05), bleeding (OR 2.18 for direct, 3.26 for graft, p < 0.05), and DVT (OR 2.12 for direct, 2.62 for graft, p < 0.05) compared to PD alone. Graft repair was further associated with increased risk of reoperation (OR 1.59), septic shock (OR 2.77) and 30-day mortality (OR 2.72), all p < 0.05. DISCUSSION: The risk of significant morbidity and mortality for PDVR is associated with the extent of vascular resection, with graft repairs having increased morbidity and mortality rates.

TIMING OF RADIOACTIVE IODINE THERAPY DOES NOT IMPACT OVERALL SURVIVAL IN HIGH-RISK PAPILLARY THYROID CARCINOMA.

OBJECTIVE: Postthyroidectomy radioiodine (RAI) therapy is indicated for papillary thyroid carcinoma (PTC) with high-risk features. There is variability in the timing of RAI therapy with no consensus. We analyzed the impact of the timing of initial RAI therapy on overall survival (OS) in PTC. METHODS: The National Cancer Data Base (NCDB) was queried from 2003 to 2006 for patients with PTC undergoing near/subtotal or total thyroidectomy and RAI therapy. High-risk patients had tumors >4 cm in size, lymph node involvement, or grossly positive margins. Early RAI was ≤3 months, whereas delayed was between 3 and 12 months after thyroidectomy. Kaplan-Meier (KM) and Cox survival analyses were performed after adjusting for patient and tumor-related variables. A propensity-matched set of high-risk patients after eliminating bias in RAI timing was also analyzed. RESULTS: There were 9,706 patients in the high-risk group. The median survival was 74.7 months. KM analysis showed a survival benefit for early RAI in high-risk patients (P = .025). However, this difference disappeared (hazard ratio [HR] 1.26, 95% confidence interval [CI] 0.98-1.62, P = .07) on adjusted Cox multivariable analysis. Timing of RAI therapy failed to affect OS in propensity-matched high-risk patients (HR 1.09, 95% CI 0.75-1.58, P = .662). CONCLUSION: The timing of postthyroidectomy initial RAI therapy does not affect OS in patients with high-risk PTC. ABBREVIATIONS: CI = confidence interval CLNM = cervical lymph node metastasis FVPTC = follicular variant papillary thyroid carcinoma HR = hazard ratio KM = Kaplan-Meier NCDB = National Cancer Data Base OS = overall survival PTC = papillary thyroid carcinoma RAI = radioactive iodine.

Using a modification of the Clavien-Dindo system accounting for readmissions and multiple interventions: defining quality for pancreaticoduodenectomy.

BACKGROUND: The Clavien-Dindo system (CD) does not change the grade assigned a complication when multiple readmissions or interventions are required to manage a complication. We apply a modification of CD accounting for readmissions and interventions to pancreaticoduodenectomy (PD). METHODS: PDs done between 1999 and 2009 were reviewed. CD grade IIIa complications requiring more than one intervention and II and IIIa complications requiring significantly prolonged lengths of stay including all 90-day readmissions were classified severe-adverse-postoperative-outcomes (SAPO). CD IIIb, IV, and V complications were also classified SAPOs. All other complications were considered minor-adverse-postoperative-outcomes (MAPO). RESULTS: Four-hundred forty three of 490 PD patients (90.4%) had either no complication or a complication of low to moderate CD grade (I, II, IIIa). When reclassified by the new metric, 92 patient-outcomes (19%) were upgraded from CD II or IIIa to SAPO. One-hundred thirty nine patients (28.4%) had a SAPO. Multivariable regression identified age >75 years, pylorus preservation and operative blood loss >1,500 ml as predictors of SAPO. Age was not associated with poor outcome using the unmodified CD system. CONCLUSIONS: Established systems may under-grade the severity of some complications following PD. We define a procedure-specific modification of CD accounting for readmissions and multiple interventions. Using this modification, advanced age, pylorus preservation, and significant blood loss are associated with poor outcome.

Validated predictive model for treatment and prognosis of adrenocortical carcinoma.

BACKGROUND: Adrenocortical carcinoma has a poor prognosis and multiple clinical, pathological, and treatment variables. Currently, we lack a prognostic and treatment calculator to determine the survival and efficacy of adjuvant chemoradiation. We aimed to validate a calculator to assess prognosis and treatment. METHODS: We searched the National Cancer Database to identify patients with adrenocortical carcinoma surgically treated from 2004 to 2020 and randomly allocated them into a training (80%) or validation set (20%). We analyzed the variables of age; sex; Charlson Comorbidity Index; insurance status; tumor size; pathologic tumor, node, and metastasis categories; surgical margins; and use of chemotherapy and radiation therapy. We used Cox regression prediction models and bootstrap coefficients to generate a mathematical model to predict 5- and 10-year overall survival. After using the area under the curve analysis to assess the model's performance, we compared overall survival in the training and validation sets. RESULTS: Multivariable analysis of the 3,480 patients included in the study revealed that all variables were significant except sex (P < .05) and incorporated into a mathematical model. The area under the curve for 5- and 10-year overall survival was 0.68 and 0.70, respectively, for the training set and 0.70 and 0.72, respectively, for the validation set. For the bootstrap coefficients, the 5- and 10-year overall survival was 6.4% and 4.1%, respectively, above the observed mean. CONCLUSION: Our model predicts the overall survival of patients with adrenocortical carcinoma based on clinical, pathologic, and treatment variables and can assist in individualizing treatment.

Uric acid accumulation in DNA-damaged tumor cells induces NKG2D ligand expression and antitumor immunity by activating TGF-ß-activated kinase 1.

DNA damage by genotoxic drugs such as gemcitabine and 5-fluorouracil (5-FU) activates the ataxia telangiectasia, mutated (ATM)-Chk pathway and induces the expression of NKG2D ligands such as the MHC class I-related chain A and B (MICA/B). The mechanisms underlying this remain incompletely understood. Here we report that xanthine oxidoreductase (XOR), a rate-limiting enzyme that produces uric acid in the purine catabolism pathway, promotes DNA damage-induced MICA/B expression. Inhibition of the ATM-Chk pathway blocks genotoxic drug-induced uric acid production, TGF-ß-activated kinase 1 (TAK1) activation, ERK phosphorylation, and MICA/B expression. Inhibition of uric acid production by the XOR inhibitor allopurinol blocks DNA damage-induced TAK1 activation and MICA/B expression in genotoxic drug-treated cells. Exogenous uric acid activates TAK1, NF-κB, and the MAP kinase pathway. TAK1 inhibition blocks gemcitabine- and uric acid-induced MAP kinase activation and MICA/B expression. Exogenous uric acid in its salt form, monosodium urate (MSU), induces MICA/B expression and sensitizes tumor cells to NK cell killing. MSU immunization with irradiated murine breast cancer cell line RCAS-Neu retards breast cancer growth in syngeneic breast cancer models and delays breast cancer development in a somatic breast cancer model. Our study suggests that uric acid accumulation plays an important role in activating TAK1, inducing DNA damage-induced MICA/B expression, and enhancing antitumor immunity.

Treatment differences at high volume centers and low volume centers in non-metastatic and metastatic adrenocortical carcinoma.

BACKGROUND: Adrenocortical carcinoma (ACC) is rare with poor survival. Do treatment and outcomes vary by volume? METHODS: NCDB (2004-2017) was searched for patients with ACC. High-volume centers (HVCs) were defined by ≥ 15 ACC and low-volume centers by ≤ 7 total cases. Multivariable Cox and logistic regression analysis were performed. RESULTS: ACC patients at HVCs were significantly more likely to have surgery, chemotherapy, and had lower 90-day readmission. HVCs were significantly more likely than LVCs to administer chemotherapy to surgical NonMetastatic (NM)-ACC patients. There was no significant difference in overall survival (OS), 90-day mortality, length of stay, or radiation treatments between the two. Operative Metastatic (M)-ACC at HVC had significantly improved OS, more chemotherapy administered, and lower 90-day mortality. CONCLUSION: NM-ACC and M-ACC treated at HVCs were more likely to have surgery and multimodality therapy. NM-ACC having surgery at HVCs and LVCs had similar OS. M-ACC at HVCs had improved OS and 90-day mortality.

H5N1 infection impairs the alveolar epithelial barrier through intercellular junction proteins via Itch-mediated proteasomal degradation.

The H5N1 subtype of the avian influenza virus causes sporadic but fatal infections in humans. H5N1 virus infection leads to the disruption of the alveolar epithelial barrier, a pathologic change that often progresses into acute respiratory distress syndrome (ARDS) and pneumonia. The mechanisms underlying this remain poorly understood. Here we report that H5N1 viruses downregulate the expression of intercellular junction proteins (E-cadherin, occludin, claudin-1, and ZO-1) in several cell lines and the lungs of H5N1 virus-infected mice. H5N1 virus infection activates TGF-ß-activated kinase 1 (TAK1), which then activates p38 and ERK to induce E3 ubiquitin ligase Itch expression and to promote occludin ubiquitination and degradation. Inhibition of the TAK1-Itch pathway restores the intercellular junction structure and function in vitro and in the lungs of H5N1 virus-infected mice. Our study suggests that H5N1 virus infection impairs the alveolar epithelial barrier by downregulating the expression of intercellular junction proteins at the posttranslational level.

Radioactive iodine does not improve overall survival for patients with aggressive variants of papillary thyroid carcinoma less than 2 cm.

BACKGROUND: Tall cell and diffuse sclerosing variants of papillary thyroid cancer are associated with aggressive features. Radioactive iodine after total thyroidectomy is poorly studied. METHODS: Patients ≥18 years in the National Cancer Data Base from 2004 to 2016 with classic papillary thyroid cancer, tall cell, or diffuse sclerosing 1 mm to 40 mm were identified. Logistic regression identified factors associated with aggressive features. Overall survival was assessed using Kaplan-Meier method and log-rank tests, after propensity score matching for clinicopathological and treatment variables. RESULTS: A total of 155,940 classic papillary thyroid cancer patients, 4,011 tall cell, and 507 diffuse sclerosing were identified. Tall cell patients represented an increasing proportion of the study population during the analysis period, whereas diffuse sclerosing and classic papillary thyroid cancer patients showed a statistically significant decline. Extrathyroidal extension and nodal involvement were more prevalent among tall cell and diffuse sclerosing patients when compared to those diagnosed with classic papillary thyroid cancer (P < .01). Adjuvant radioactive iodine was less frequently used in patients with classic papillary thyroid cancer when compared to tall cell and diffuse sclerosing patients (42.6% vs 62.4%, 59.0%; P < .001, respectively). Aggressive variants receiving total thyroidectomy versus total thyroidectomy + radioactive iodine propensity score matched across clinicopathologic variables were analyzed. There was no difference in overall survival between the 2 treatment groups for tumors <2 cm (01-1.0 cm, 92.2% vs 84.8%; P = .98); (1.0-2.0 cm, 72.7% vs 88.1%; P = .82). However, overall survival was improved for total thyroidectomy + radioactive iodine propensity score matched patients with tumor sizes 21 to 40 mm versus total thyroidectomy (83.4% vs 70.0%, P = .004). CONCLUSION: For aggressive tumor variants ≤2 cm treated with total thyroidectomy, there is no overall survival advantage provided by the addition of adjuvant radioactive iodine.

Overall survival is improved with total thyroidectomy and radiation for male patients and patients older than 55 with T2N0M0 Stage 1 classic papillary thyroid cancer.

BACKGROUND: We examine whether surgery extent and radiation administration affect overall survival for cT2N0M0 classic papillary thyroid cancer according to age and sex. METHODS: Patients with cT2N0M0 classic papillary thyroid cancer tumors in the National Cancer Data Base (2004-2016) were selected. Multivariable Cox regression analysis compared patients (combined male + female cohorts) having lobectomy to those having total thyroidectomy with or without radiation (primarily radioactive iodine) for ages: 18 to 45, 46 to 55, and >55 years. In addition, 1:1 propensity score matching and Kaplan-Meier curves with 10-year overall survival estimates, and log-rank test were stratified by age and sex. RESULTS: Lobectomy had equivalent overall survival to total thyroidectomy without and with radiation for patients (combined male + female cohorts) aged 18 to 45 and 46 to 55 years on multivariable analysis. On propensity score matching there was overall survival advantage for total thyroidectomy with radiation over both lobectomy and total thyroidectomy for men (ages 18-90+ combined) and overall survival advantage in patients (combined male + female cohort) aged >55 years having total thyroidectomy with radiation versus lobectomy. On propensity score matching there were no overall survival differences in women (ages 18-90+ combined) or patients (combined male + female cohort) aged 18 to 45 and 46 to 55 years having either lobectomy, total thyroidectomy, or total thyroidectomy with radiation. CONCLUSION: For cT2N0M0 classic papillary thyroid cancer, total thyroidectomy with radiation improves 10-year overall survival for patients (combined male + female cohort) aged >55 years and men (ages 18-90+ combined).

Major histocompatibility complex class I-related chain A/B (MICA/B) expression in tumor tissue and serum of pancreatic cancer: role of uric acid accumulation in gemcitabine-induced MICA/B expression.

BACKGROUND: Major histocompatibility complex class I-related chain A and B (MICA/B) are two stress-inducible ligands that bind the immunoreceptor NKG2D and play an important role in mediating the cyotoxicity of NK and T cells. In this study, we sought to study MICA/B expression in pancreatic cancer and to determine whether and how genotoxic drugs such as gemcitabine can affect MICA/B expression and natural killer cytotoxity. METHODS: Seven pancreatic cancer cell lines were analyzed for MICA/B expression by flow cytometry and for their sensitivity to NK-92 cell killing by a 51Cr release assay. MICA/B expression in tumor tissues and sera of pancreatic cancer was analyzed by immunohistochemical staining (IHC) and ELISA, respectively. RESULTS: Two MICA/B-positive cell lines were sensitive to the cytotoxic activity of NK-92 cells. Other two MICA/B-positive cell lines and three MICA/B-negative cell lines were resistant to NK-92 cell killing. MICA/B expression was positive in 17 of 25 (68%) pancreatic ductal adenocarcinomas but not in normal pancreatic ductal epithelial cells. Serum MICA/B levels were significantly elevated in patients with pancreatic adenocarcinomas but did not correlate with the stage of pancreatic cancer and patient survival. Gemcitabine therapy led to increased serum MICA levels in 6 of 10 patients with detectable serum MICA. Allopurinol, an inhibitor of xanthine oxidoreductase that converts xanthine to uric acid, blocked uric acid production, MICA/B expression, and sensitivity to NK-92 cell killing toward a PANC-1 cancer cell line exposed to radiation and two genotoxic drugs, gemcitabine and 5-fluorouracil. CONCLUSIONS: The levels of MICA/B expression in serum and tissue of pancreatic cancer are elevated. DNA damage-induced MICA/B expression is mediated through increased uric acid production.