The potential of high-order features of routine blood test in predicting the prognosis of non-small cell lung cancer.

BACKGROUND: Numerous studies have demonstrated that the high-order features (HOFs) of blood test data can be used to predict the prognosis of patients with different types of cancer. Although the majority of blood HOFs can be divided into inflammatory or nutritional markers, there are still numerous that have not been classified correctly, with the same feature being named differently. It is an urgent need to reclassify the blood HOFs and comprehensively assess their potential for cancer prognosis. METHODS: Initially, a review of existing literature was conducted to identify the high-order features (HOFs) and classify them based on their calculation method. Subsequently, a cohort of patients diagnosed with non-small cell lung cancer (NSCLC) was established, and their clinical information prior to treatment was collected, including low-order features (LOFs) obtained from routine blood tests. The HOFs were then computed and their associations with clinical features were examined. Using the LOF and HOF data sets, a deep learning algorithm called DeepSurv was utilized to predict the prognostic risk values. The effectiveness of each data set's prediction was evaluated using the decision curve analysis (DCA). Finally, a prognostic model in the form of a nomogram was developed, and its accuracy was assessed using the calibration curve. RESULTS: From 1210 documents, over 160 blood HOFs were obtained, arranged into 110, and divided into three distinct categories: 76 proportional features, 6 composition features, and 28 scoring features. Correlation analysis did not reveal a strong association between blood features and clinical features; however, the risk value predicted by the DeepSurv LOF- and HOF-models is significantly linked to the stage. Results from DCA showed that the HOF model was superior to the LOF model in terms of prediction, and that the risk value predicted by the blood data model could be employed as a complementary factor to enhance the prognosis of patients. A nomograph was created with a C-index value of 0.74, which is capable of providing a reasonably accurate prediction of 1-year and 3-year overall survival for patients. CONCLUSIONS: This research initially explored the categorization and nomenclature of blood HOF, and proved its potential in lung cancer prognosis.

The role of aldosterone and ideal cardiovascular health in incident cardiovascular disease: The Jackson heart study.

Background: Higher levels of ideal cardiovascular health (ICH) are associated with lower levels of aldosterone and incidence of cardiovascular disease (CVD). However, the degree to which aldosterone mediates the association between ICH and CVD incidence has not been explored. Thus, we investigated the mediational role of aldosterone in the association of 5 components of ICH (cholesterol, body mass index (BMI), physical activity, diet and smoking) with incident CVD and the mediational role of blood pressure (BP) and glucose in the association of aldosterone with incident CVD in a cohort of African Americans (AA). Methods: The Jackson Heart Study is a prospective cohort of AAs adults with data on CVD outcomes. Aldosterone, ICH metrics and baseline characteristics were collected at exam 1 (2000-2004). ICH score was developed by summing 5 ICH metrics (smoking, dietary intake, physical activity, BMI, and total cholesterol) and grouped into two categories (0-2 and ≥3 metrics). Incident CVD was defined as stroke, coronary heart disease, or heart failure. Cox proportional hazard regression models were used to model the association of categorical ICH score with incident CVD. The R Package Mediation was utilized to examine: 1) The mediational role of aldosterone in the association of ICH with incident CVD and 2) The mediational role of blood pressure and glucose in the association of aldosterone with incident CVD. Results: Among 3,274 individuals (mean age: 54±12.4 years, 65% female), there were 368 cases of incident CVD over a median of 12.7 years. The risk of incident CVD was 46% lower (HR: 0.54; 95%CI 0.36, 0.80) in those with ≥3 ICH metrics at baseline compared to 0-2. Aldosterone mediated 5.4% (p = 0.006) of the effect of ICH on incident CVD. A 1-unit increase in log-aldosterone was associated with a 38% higher risk of incident CVD (HR 1.38, 95%CI: 1.19, 1.61) with BP and glucose mediating 25.6% (p<0.001) and 4.8% (p = 0.048), respectively. Conclusion: Aldosterone partially mediates the association of ICH with incident CVD and both blood pressure and glucose partially mediate the association of aldosterone with incident CVD, emphasizing the potential importance of aldosterone and ICH in risk of CVD among AAs.

The role of aldosterone and ideal cardiovascular health in incident diabetes: The Jackson Heart Study.

Background: Greater attainment of ideal cardiovascular health (ICH) and lower serum aldosterone are associated with lower diabetes risk. Higher levels of ICH are associated with lower aldosterone. The mediational role of aldosterone in the association of ICH with incident diabetes remains unexplored. Thus, we examined the mediational role of aldosterone in the association of 5 ICH components (smoking, diet, physical activity, body mass index [BMI], and cholesterol) with incident diabetes. Additionally, we investigated the mediational role of glucose and blood pressure (BP) in the association of aldosterone with incident diabetes in an African American (AA) cohort. Methods: We conducted a prospective cohort analysis among AA adults, aged 21-94 years, in the Jackson Heart Study. Data on ICH, aldosterone, and cardiometabolic risk factors were collected at exam 1 (2000-2004). Diabetes (fasting glucose ≥ 126 mg/dL, physician diagnosis, use of diabetes drugs, or glycated hemoglobin ≥ 6.5%) was assessed at exams 1 through 3 (2009-2012). ICH metrics were defined by American Heart Association 2020 goals for smoking, dietary intake, physical activity, BMI, total cholesterol, BP and glucose. The number of ICH metrics attained at exam 1, excluding BP and fasting glucose, were summed (0-2, vs. 3+). R Package Mediation was used to examine: 1) The mediational role of aldosterone in the association of ICH with incident diabetes; and 2) the mediational role of BP and glucose in the association of aldosterone with incident diabetes. Results: Among 2,791 participants (mean age: 53±12, 65% female) over a median of 7.5 years, there were 497 incident diabetes cases. Risk of incident diabetes was 37% (HR: 0.63, 95%CI: 0.47, 0.84) lower in 3+ ICH category compared to 0-2 ICH category. Aldosterone mediated 6.98% (95% CI: 1.8%, 18.0%) of the direct effect of ICH on incident diabetes. A 1-unit increase in log-aldosterone was associated with a 44% higher risk of diabetes (HR 1.44, 95%CI 1.25-1.64). BP and glucose mediated 16.3% (95% CI: 7.0%, 31.0%) and 19.7% (95% CI: 6.5%, 34.0%) of the association of aldosterone with incident diabetes, respectively. Conclusion: Aldosterone is a mediator of the association of ICH with incident diabetes, whereas BP and glucose are mediators of the association of aldosterone with incident diabetes, emphasizing the importance of the renin-angiotensin-aldosterone system and ICH in lowering risk of diabetes in AA populations.

[Safety and efficacy of different doses of tranexamic acid in posterior cervical laminectomy with lateral mass screw fixation and bone graft fusion].

Objective: To investigate the safety and efficacy of different doses of tranexamic acid (TXA) in posterior cervical laminectomy with lateral mass screw fixation and bone graft fusion by a prospective clinical study. Methods: The middle-aged and elderly patients with cervical spondylotic myelopathy, who were admitted between January 2020 and January 2022 and scheduled to undergo posterior cervical laminectomy with lateral mass screw fixation and bone graft fusion, were studied as the research subjects. Among them, 165 patients met the selection criteria and were included in the study. The patients were allocated into 3 groups ( n=55) by random double-blind lottery. Groups A and B were given intravenous infusion of TXA at 30 minutes before operation according to the standards of 15 and 30 mg/kg, respectively; and group C was given normal saline in the same way. There was no significant difference in gender, age, body mass index, and preoperative D-dimer, hemoglobin (Hb), and hematocrit (HCT) between groups ( P>0.05). The intraoperative bleeding, intraoperative blood transfusion, postoperative drainage volume, drainage days, and postoperative hospital stay were recorded. The Hb, HCT, and D-dimer were compared before operation and at 3 days after operation. Venous ultrasonography of the lower extremities was taken after operation to assess thrombosis; and the postoperative hematoma and epilepsy were also observed. Results: All operations were successfully completed, and the incisions healed by first intention. The differences in intraoperative bleeding volume, postoperative drainage volume, drainage days, and postoperative hospital stay between groups were significant ( P<0.05). The above indexes were significantly less in group B than in groups A and C. During operation, 14 patients in group A and 23 patients in group C were transfused, and no patient in group B had blood transfusions. Compared with groups A and C, the blood transfusion volume in group B significantly decreased ( P<0.05), and the difference between groups A and C was not significant ( P>0.05). There was no significant difference in the differences of D-dimer, Hb, and HCT before and after operation between groups ( P>0.05). At 5 days after operation, the venous ultrasonography of the lower extremities showed that the 2 cases of intermuscular venous thrombosis occurred in groups A, B, and C, respectively. No hematoma or epilepsy occurred after operation. Conclusion: The application of 15 and 30 mg/kg TXA in posterior cervical laminectomy with lateral mass screw fixation and bone graft fusion can reduce intraoperative bleeding and postoperative drainage volume, postoperative drainage days, and postoperative hospital stay. And application of 30 mg/kg TXA can reduce intraoperative blood transfusion, without increasing the risk of lower extremity venous thrombosis, hematoma, and epilepsy.

PentaRay® Multielectrode Mapping Catheter for Atrial Tachyarrhythmia in Adults With Congenital Heart Disease.

BACKGROUND: Ablation of atrial tachyarrhythmia in adults with congenital heart disease (ACHD) is challenging because of complex anatomy and high scar burden. We proposed that the addition of high-density mapping with the PentaRay® (Biosense Webster, Inc) mapping catheter (EAM+P) to 3-dimensional electroanatomic mapping (EAM) allows for rapid acquisition of high-resolution maps and shorter procedure times. METHODS: In this single-center, retrospective cohort study of patients with ACHD who underwent atrial arrhythmia ablation, patients were divided those who underwent ablation with EAM and those who underwent ablation with EAM+P. RESULTS: Fifteen ablations were performed in 13 patients using standard EAM, and 11 ablations were performed in 10 patients using EAM+P. There was no difference in mean age or complexity of congenital heart disease. The procedure duration was 1.5 times longer in the EAM than in the EAM+P group (P = .015). The dose area product was 12 times higher in the EAM than in the EAM+P group (P = .001). A higher number of venous access sites were used for EAM cases than for EAM+P cases (P = .008). Acute success rates of ablation and recurrence rates at 1 year were similar in the 2 groups. There were no procedure-related complications in either group. CONCLUSION: This is the first study to evaluate the use of the PentaRay® high-density mapping catheter for ablation of atrial tachyarrhythmia in patients with ACHD. The use of the PentaRay® high-density mapping catheter results in shorter procedure time, decreased radiation exposure, and fewer venous access sites.

Phase I study of trametinib in combination with whole brain radiation therapy for brain metastases.

INTRODUCTION: Trametinib is a MEK inhibitor with intracranial activity indicated for BRAF-mutant metastatic malignancies. Yet, the safety of trametinib concurrent with whole brain radiation therapy (WBRT) is unknown. We performed a single-institution, prospective, 3 + 3, phase I clinical trial to determine the maximum tolerated dose (MTD) of trametinib with WBRT. METHODS AND MATERIALS: Patients with brain metastases (BM) received daily trametinib for 28 days, starting 7 days prior to and continuing through WBRT (37.5 Gy/15 fractions). Dose levels (DL)1-3 were 1.0, 1.5, and 2.0 mg. The MTD of trametinib plus WBRT, the max dose where ≤1 of 6 patients experienced a dose limiting toxicity (DLT), was the primary endpoint. RESULTS: 10 patients were enrolled (median age-59 [47-64], BM-5 [1-10], 50% melanoma). Three and 7 patients were assigned to DL1 and 2. One DL2 patient withdrew. 89% of remaining patients completed therapy per protocol, but 1 DL2 patient with systemic progression discontinued therapy at 30 Gy. Thirteen grade (G)3-4 toxicities were observed, of which 12 occurred at DL2 (4/6 of patients). DLT was reached at DL2 (G4 thrombocytopenia and G3 diarrhea, 1 each). There were no G5 toxicities. Median overall survival was 2.2 months. During the study period, changing practice patterns favored utilization of stereotactic radiosurgery (SRS). Thus, the trial closed early prior to completion. CONCLUSIONS: In a patient population representative of modern candidates for WBRT, trametinib plus WBRT is highly toxic with a MTD <1.5 mg. The safety of trametinib with SRS remains an important question for future study.

Workforce demographics and unit structure in paediatric cardiac critical care in the United States.

OBJECTIVE: To assess current demographics and duties of physicians as well as the structure of paediatric cardiac critical care in the United States. DESIGN: REDCap surveys were sent by email from May till August 2019 to medical directors ("directors") of critical care units at the 120 United States centres submitting data to the Society of Thoracic Surgeons Congenital Heart Surgery Database and to associated faculty from centres that provided email lists. Faculty and directors were asked about personal attributes and clinical duties. Directors were additionally asked about unit structure. MEASUREMENTS AND MAIN RESULTS: Responses were received from 66% (79/120) of directors and 62% (294/477) of contacted faculty. Seventy-six percent of directors and 54% of faculty were male, however, faculty <40 years old were predominantly women. The majority of both groups were white. Median bed count (n = 20) was similar in ICUs and multi-disciplinary paediatric ICUs. The median service expectation for one clinical full-time equivalent was 14 weeks of clinical service (interquartile range 12, 16), with the majority of programmes (86%) providing in-house attending night coverage. Work hours were high during service and non-service weeks with both directors (37%) and faculty (45%). CONCLUSIONS: Racial and ethnic diversity is markedly deficient in the paediatric cardiac critical care workforce. Although the majority of faculty are male, females make up the majority of the workforce younger than 40 years old. Work hours across all age groups and unit types are high both on- and off-service, with most units providing attending in-house night coverage.

Tricuspid Valve and Right Ventricular Function Throughout the Hybrid Palliation Strategy for Hypoplastic Left Heart Syndrome and Variants.

BACKGROUND: Tricuspid valve (TV) and right ventricular (RV) function are major determinants of morbidity and mortality in patients with hypoplastic left heart syndrome (HLHS). We sought to retrospectively evaluate these parameters throughout the hybrid palliation strategy. METHODS: From 2002 to 2018, 203 patients with HLHS and variants presented for hybrid stage I (HS1). Echocardiographic evaluation of tricuspid regurgitation (TR) and RV function was assessed at multiple time points. Clinical outcomes including tricuspid valvuloplasty, transplantation, and death were reviewed. RESULTS: The most prevalent HLHS subtype was aortic atresia/mitral atresia. The presence of significant TR and/or RV dysfunction was 14.78% and 9.36%, respectively, at the time of initial HS1. There were 185 survivors following HS1 (91.13%, n = 185/203), while 147 patients underwent comprehensive stage II or bidirectional Glenn shunt (72.41%, n = 147/203). Tricuspid valvuloplasty was undertaken in nine patients (4.86%, n = 9/185). Ultimately, 100 patients underwent the Fontan procedure. The odds of development of significant TR and/or RV dysfunction were not statistically different throughout the stages of palliation (TR: odds ratio [OR] = 0.14-0.25, P = .5260; RV dysfunction: OR = 0.02-0.13, P = .3992). However, the risk of death and/or transplant was 2.5- to 3.8-fold when either were present alone or in combination (TR: OR = 2.58, P = .0356; RV dysfunction: OR = 3.84, P = .0262). Transplant-free survival at 15 years was 44.8%. CONCLUSION: Following hybrid palliation for HLHS, the majority of survivors have normal RV and TV functions. Tricuspid valvuloplasty was required in few patients. Once significant TR and/or RV dysfunction ensues, there is a two- to three-fold risk of death and/or transplant.

Incidence and impact of acute kidney injury in patients with hypoplastic left heart syndrome following the hybrid stage 1 palliation.

OBJECTIVE: Acute kidney injury leads to worse outcomes following paediatric cardiac surgery. There is a lack of literature focusing on acute kidney injury after the Hybrid stage 1 palliation for single ventricle physiology. Patients undergoing the Hybrid Stage 1, as a primary option, may have a lower incidence of kidney injury than previously reported. When present, kidney injury may increase the risk of post-operative morbidity and mortality. METHODS: A retrospective, single centre review was conducted in patients with hypoplastic left heart syndrome who underwent Hybrid Stage 1 from 2008 to 2018. Acute kidney injury was defined as a dichotomous yes (meeting any injury criteria) or no (no injury) utilising two different criteria utilised in paediatrics. The impact of kidney injury on perioperative characteristics and 30-day mortality was analysed. RESULTS: The incidence of acute kidney injury is 13.4-20.7%, with a severe injury rate of 2.4%. Patients without a prenatal diagnosis of hypoplastic left heart syndrome have a higher incidence of kidney injury than those prenatally diagnosed, (40% versus 14.5%, p = 0.024). Patients with acute kidney injury have a significantly higher incidence of 30-day mortality, 27.3%, compared to without, 5.6% (p = 0.047). DISCUSSION: The incidence of severe acute kidney injury after the Hybrid Stage 1 palliation is low. A prenatal diagnosis may be associated with a lower incidence of kidney injury following the Hybrid Stage 1. Though uncommon, severe acute kidney injury following Hybrid Stage 1 may be associated with higher 30-day mortality.

A Pilot Trial Evaluating Stereotactic Body Radiation Therapy to Induce Hyperemia in Combination With Transarterial Chemoembolization for Hepatocellular Carcinoma.

PURPOSE: Despite the survival benefit of transarterial chemoembolization (TACE) for unresectable hepatocellular carcinoma (HCC), a majority of tumors recur, attributed to hypovascularity and treatment resistance. Preclinical studies show that moderate radiation doses induce changes in tumor permeability and perfusion, suggesting an opportunity for TACE sensitization by radiation. In this prospective phase 1 trial, we evaluated the feasibility, safety, tolerability, response, and functional magnetic resonance imaging (MRI) changes associated with single-fraction stereotactic body radiation therapy (SBRT) followed by TACE within 24 hours. METHODS AND MATERIALS: Patients with HCC, 1 to 3 lesions, Childs-Pugh A/B liver function, and no major vascular invasion were enrolled. The primary objective was to establish the feasibility of single-dose SBRT (7.5 or 10 Gy) followed by TACE within 24 hours. Secondary endpoints included safety, tolerability, perfusional changes via functional MRI, overall response rate (ORR), clinical benefit rate (CBR), freedom from local progression, progression-free survival, and overall survival. RESULTS: Sixteen patients were enrolled, and 13 received SBRT and TACE. Median follow-up was 15.3 months. Best overall ORR and CBR were 76.9% and 92.3%, respectively. The 1- and 3-month ORR was 76.9% and 69.2%, respectively, and 1- and 3-month CBR was 92.3% and 69.2%, respectively. Median overall survival, progression-free survival, and freedom from local progression were 14.0, 5.2, and 5.9 months, respectively. Crude rates of grade 1+ and grade 2+ toxicity were 85% and 38%, respectively. No grade 3 to 4 toxicities were recorded. One grade 5 toxicity occurred due to hemorrhage 4 days after TACE. On dynamic contrast-enhanced MRI, the transfer rate constant from blood plasma to extracellular extravascular space (kpe) increased within 6 hours post-SBRT but decreased by 24 hours. CONCLUSIONS: We hypothesized a strategy of SBRT preceding TACE for the purpose of enhancing TACE delivery and efficacy and tested this strategy in a small pilot study. We found that single-dose SBRT followed by TACE within 24 hours is feasible and tolerable. Dynamic contrast-enhanced MRI revealed acute changes in tumor permeability/perfusion after SBRT. Additional studies are needed to establish the safety and efficacy of this combination and the effects of SBRT on the HCC microenvironment.

Activity of PD1 inhibitor therapy in advanced sarcoma: a single-center retrospective analysis.

BACKGROUND: Sarcomas constitute a heterogeneous group of tumors with different clinical behaviors and variable responses to systemic therapies. Recent immunotherapy studies with PD1 inhibitors (PD1i) show promising results with use in certain soft-tissue sarcomas; however, the clinical and molecular features that best predict response to PD1i remain unclear. METHODS: Demographic, imaging, histologic, and genetic sequencing data was collected for sarcoma patients who received nivolumab or pembrolizumab (PD1i) treatment at our institution between January 1st 2015 and April 23rd 2018. The primary objective was to determine progression-free survival (PFS) in patients with advanced sarcomas receiving PD1i. Secondary objectives included determining overall survival (OS) and assessment of characteristics associated with response to PD1i. Fifty-six patients who were treated with PD1i therapy met inclusion criteria for this study. RESULTS: Partial response towards PD1i treatment was seen in 3 in 26 evaluable patients, but no complete responses were observed (overall response rate 11.5%). Within this group of patients, the 90 day PFS was found to be 48.8%. In patients in whom PD1 expression was known, there was a statistically significant positive correlation between expression of PD1 and longer PFS and OS rates. Patients that were treated with more than four cycles of PD1i therapy were also more likely to have a greater OS. CONCLUSIONS: This study suggests activity of PD1i in a pretreated cohort of advanced sarcoma patients, particularly for the subset of patients with PD1 positive tumors. Our results highlight the importance of further research to better target the optimal patient population and markers of response.

Mode of anesthesia and major perioperative outcomes associated with vaginal surgery.

INTRODUCTION AND HYPOTHESIS: The primary aim was to compare the incidence of major perioperative complications in women undergoing vaginal reconstructive surgery with general, regional, and monitored anesthesia care using a national database. The secondary aim was to compare length of hospital stay, 30-day readmission rates, urinary tract infections, and reoperation rates between anesthesia types. MATERIALS AND METHODS: The National Surgical Quality Improvement Program database was used to study women undergoing vaginal surgery for pelvic floor disorders from 2006 to 2015 via Current Procedural Terminology codes. Demographic and clinical variables were abstracted. The incidence of major perioperative complications was defined as the occurrence of any of the following within 30 days of surgery: death, surgical-site infection, pneumonia, venous thromboembolism, intensive care unit admission, stroke, transfusion, sepsis, and myocardial infarction. Regression analysis was used to estimate the relative risks (RR) associated with anesthesia type for each outcome. RESULTS: From the database, we gathered data on 37,426 women who underwent vaginal reconstructive surgery between 2006 and 2015; 87.2% (n = 32,623) underwent general, 6.9% (n = 2565) regional, and 5.9% (n = 2238) monitored anesthesia care. Major perioperative complications occurred in 560 women (1.5%). Relative to general anesthesia, the adjusted risk of major perioperative complications was not significantly different in those receiving monitored or regional anesthesia [monitored vs. general, adjusted RR 0.74, 95% confidence interval (CI) 0.45-1.20; regional vs. general, adjusted RR 1.23, 95% CI 0.92-1.65]. DISCUSSION: Major perioperative complications in vaginal reconstructive surgery were uncommon, and no differences were observed between monitored, regional, and general anesthesia outcomes.

Stereotactic body radiation therapy is associated with improved overall survival compared to chemoradiation or radioembolization in the treatment of unresectable intrahepatic cholangiocarcinoma.

BACKGROUND: Intrahepatic cholangiocarcinoma (ICC) is a highly lethal malignancy. For patients with locally advanced, unresectable disease, numerous liver-directed therapy options exist, including chemoradiation (CRT), stereotactic body radiation therapy (SBRT), and transarterial radioembolization (TARE). There is no randomized data to inform clinicians regarding the optimal treatment modality. METHOD: We used the National Cancer Database (NCDB) to study the overall survival (OS) of patients with ICC treated with CRT, SBRT, and TARE. We used Cox proportional hazards modeling and inverse probability of treatment weighting (IPTW) to account for confounding variables. RESULTS: We identified 170 patients with unresected ICC treated with SBRT (n = 37), CRT (n = 61), or TARE (n = 72). SBRT was associated with higher OS compared to CRT (hazard ratio [HR] = 0.37; 95% confidence interval [CI] 0.20-0.68; p = 0.001) and TARE (HR = 0.40; 95% CI 0.22-0.74; p = 0.003). On multivariable analysis, SBRT remained associated with higher OS compared to CRT (HR = 0.44; 95% CI 0.21-0.91; p = 0.028) and TARE (HR = 0.42; 95% CI 0.21-0.84; p = 0.014). After IPTW (Bonferroni-adjusted significance threshold, α = 0.017), SBRT again had a statistically significant association with higher OS compared to CRT (HR = 0.22; 95% CI 0.11-0.44; p < 0.0001) and was nominally associated TARE (HR = 0.58; 95% CI 0.37-0.91; p = 0.019). CONCLUSIONS: We found SBRT is associated with higher OS when compared to CRT or TARE for the treatment of unresectable ICC. Due to the retrospective nature of the study and potential selection bias, these findings should be evaluated prospectively.

Association of Liver-Directed Local Therapy With Overall Survival in Adults With Metastatic Intrahepatic Cholangiocarcinoma.

Importance: Intrahepatic cholangiocarcinoma is an aggressive hepatobiliary malignant neoplasm characterized by local progression and frequent metastasis. Definitive local therapy to the liver in the setting of metastatic intrahepatic cholangiocarcinoma may improve overall survival. Objective: To compare the overall survival of patients with metastatic intrahepatic cholangiocarcinoma treated with chemotherapy alone vs chemotherapy with definitive liver-directed local therapy. Design, Setting, and Participants: This cohort study used the National Cancer Database to identify 2201 patients with metastatic intrahepatic cholangiocarcinoma diagnosed between January 2004 and December 2014 who received chemotherapy with or without hepatic surgery or external beam radiation to a dose 45 Gy or higher. Multiple imputation, Cox proportional hazards, propensity score matching, and landmark analysis were used to adjust for confounding variables. Analyses were performed between September 2018 and February 2019. Exposures: Chemotherapy alone and chemotherapy with liver-directed surgery or radiation. Main Outcomes and Measures: Overall survival. Results: A total of 2201 patients (1131 [51.4%] male; median [interquartile range] age, 63 [55-71] years) who received chemotherapy alone (2097 [95.3%]) or chemotherapy with liver-directed local therapy (total, 104 [4.7%]; surgery, 76 [73.1%]; radiation, 28 [26.9%]) were identified. Patients treated with chemotherapy alone had larger median (interquartile range) primary tumor size (7.0 [4.4-10.0] cm vs 5.6 [4.0-8.3] cm; P = .048) and higher frequency of lung metastases (383 [25.9%] vs 7 [6.7%]; P = .004). Patients treated with liver-directed local therapy had higher frequency of distant lymph node metastases (34 [32.7%] vs 528 [25.2%]; P = .045). Liver-directed local therapy was associated with higher overall survival compared with chemotherapy alone on multivariable analysis (hazard ratio [HR], 0.60; 95% CI, 0.48-0.74; P < .001). A total of 208 patients treated with chemotherapy alone were propensity score matched with 104 patients treated with chemotherapy plus liver-directed local therapy. Liver-directed local therapy continued to be associated with higher overall survival (HR, 0.57; 95% CI, 0.44-0.74; P < .001), which persisted on landmark analysis at 3 months (HR, 0.61; 95% CI, 0.47-0.79; log-rank P < .001), 6 months (HR, 0.68; 95% CI, 0.50-0.92; log-rank P = .01), and 12 months (HR, 0.68; 95% CI, 0.47-0.98; log-rank P = .04). Conclusions and Relevance: In this study, the addition of hepatic surgery or irradiation to chemotherapy was associated with higher overall survival when compared with chemotherapy alone in patients with metastatic intrahepatic cholangiocarcinoma. These findings may be valuable given the paucity of available data for this disease and should be validated in an independent cohort or prospective study.

Pre-treatment serum bicarbonate predicts for primary tumor control after stereotactic body radiation therapy in patients with localized non-small cell lung cancer.

BACKGROUND: Tumor aggressiveness and hypoxia are linked to acidosis in the tumor microenvironment (TME). We hypothesized that low pre-treatment serum bicarbonate, potentially correlating with an acidic and hypoxic TME, predicts for poor outcomes after stereotactic body radiation therapy (SBRT) for non-small cell lung cancer (NSCLC). METHODS: We included patients with localized NSCLC treated to a biologically effective dose (BED) ≥ 100 Gy, with available pre-treatment bicarbonate values within 3 months of treatment. We used receiver operating characteristic analysis to determine the bicarbonate concentration optimally predicting for primary tumor recurrence, and evaluated its association with recurrence and survival. We validated our findings in an independent cohort of patients from three collaborating institutions. RESULTS: A total of 110 patients and 114 tumors were included in the training cohort, with median follow-up of 15.0 months. Bicarbonate < 26 mEq/L was associated with primary tumor recurrence on univariate (HR = 5.92; 95% CI 1.69-24.88; p = 0.005) and multivariate analysis (HR = 5.48; 95% CI 1.37-25.19; p = 0.020). The validation cohort consisted of 195 patients and 208 tumors with median follow-up of 27.5 months. In the validation cohort, bicarbonate < 26 mEq/L was again associated with primary tumor recurrence on univariate (HR = 3.38; 95% CI 1.27-9.37; p = 0.015) and multivariate analysis (HR = 3.33; 1.18-10.07; p = 0.023). CONCLUSIONS: Pre-treatment bicarbonate predicts for primary tumor control in NSCLC treated with SBRT and may be useful for risk stratification. These findings should be confirmed prospectively.

The Association of Life's Simple 7 with Aldosterone among African Americans in the Jackson Heart Study.

BACKGROUND: Among African Americans (AAs), attaining higher levels of American Heart Association (AHA) ideal cardiovascular health (Life's Simple 7 [LS7]) is associated with lower risk of diabetes and cardiovascular disease (CVD). We previously showed that aldosterone is associated with higher risk of diabetes and CVD in AAs. Thus, we investigated the association of LS7 metrics with aldosterone in the Jackson Heart Study (JHS). METHODS: Ideal metrics were defined by AHA 2020 goals for health behaviors (smoking, dietary intake, physical activity, and body mass index) and health factors (total cholesterol, blood pressure, and fasting glucose). The number of ideal LS7 metrics attained at baseline were summed into a continuous score (0-7) and categorical groups (Poor: 0-1, Intermediate: 2-3, and Ideal: ≥4 ideal LS7 metrics). Multivariable linear regression was used. RESULTS: Among 4,095 JHS participants (mean age 55 ± 13 years, 65% female), median serum aldosterone was 4.90, 4.30, and 3.70 ng/dL in the poor (n = 1132), intermediate (n = 2288) and ideal (n = 675) categories respectively. Aldosterone was 15% [0.85 (0.80, 0.90)] and 33% [0.67 (0.61, 0.75)] lower in the intermediate and ideal LS7 categories compared to the poor LS7 category. Each additional LS7 metric attained on continuous LS7 score (0-7) was associated with an 11% [0.89 (0.86, 0.91)] lower aldosterone level with variation by sex with women having a 15% lower aldosterone vs. 5% in men. CONCLUSIONS: Higher attainment of ideal LS7 metrics was associated with lower serum aldosterone among AAs with a greater magnitude of association among women compared to men.

Pre-treatment neutrophil-lymphocyte ratio is associated with overall mortality in localized non-small cell lung cancer treated with stereotactic body radiotherapy.

BACKGROUND: Neutrophil-lymphocyte ratio (NLR) has been associated with mortality in several disease sites. We hypothesized that NLR is associated with inferior outcomes in localized non-small cell lung cancer (NSCLC) treated with stereotactic body radiotherapy (SBRT). METHODS: We evaluated the association of pre-treatment NLR, obtained within 6 months of starting SBRT, with overall survival, as well as primary tumor, regional, and distant recurrence. Multivariate Cox regression was then used to assess pre-treatment NLR as a predictor of mortality. We validated our findings in an independent cohort of patients treated at two other institutions. In a secondary analysis, we also evaluated the association of post-treatment NLR with mortality in the training cohort. RESULTS: A total of 156 patients and 166 tumors were included in the training cohort with a median follow-up of 13.4 months. After dichotomization by median, NLR > 3.6 was associated with mortality on univariate (p = 0.010) and multivariate analysis (p = 0.023). In the validation cohort, NLR > 3.6 was similarly associated with mortality on univariate (p = 0.031) and multivariate (p = 0.007) analysis. In a secondary analysis in the training cohort, we found post-treatment NLR was significantly increased compared to pre-treatment NLR (p < 0.001) and associated with mortality on univariate analysis (p = 0.005) and multivariate analysis (p = 0.010). CONCLUSIONS: Pre-treatment NLR > 3.6 is associated with mortality in patients treated with SBRT. This finding was validated in an independent cohort of patients treated at two other institutions. Additionally, post-treatment NLR was significantly increased from pre-treatment and associated with overall survival.

Predicting transient hypocalcemia in patients with unplanned parathyroidectomy after thyroidectomy.

OBJECTIVE: To assess the utility of rapid parathyroid hormone (PTH) values in predicting transient post-operative hypocalcemia in patients with unplanned parathyroidectomy during total or completion thyroidectomy. METHODS: All patients who underwent total or completion thyroidectomy between January 2010 and January 2015 were reviewed. Incidences of post-operative hypocalcemia were compared in patients with and without unplanned parathyroidectomy. Unplanned parathyroidectomy was defined as intra-operative incidental or intentional parathyroidectomy. Logistic regression assessed for predictors of hypocalcemia and optimum amount of calcium supplementation. RESULTS: Thirty-eight (13.6%) patients had evidence of incidental parathyroidectomy and 39/280 (13.9%) patients had parathyroid autotransplantation intra-operatively. Central neck dissection and malignancy were identified as risk factors for unplanned parathyroidectomy (p = 0.001, p = 0.060). Patients with unplanned parathyroidectomy were more likely to have hypocalcemia (p = 0.002) and hypoparathyroidism (p < 0.0005). PTH value was the only significant predictor of hypocalcemia in these patients. In patients with a post-operative PTH of ≤15, initial calcium supplementation ≥ 1000 mg decreased the risk of hypocalcemia (p < 0.05). CONCLUSION: Post-operative PTH value predicts hypocalcemia in patients undergoing total and completion thyroidectomy with unplanned parathyroidectomy. In patients with a post-operative PTH < 15, initial calcium supplementation with ≥1000 mg of elemental calcium is recommended.

Acidic pH promotes oxidation-induced dissociation of C-reactive protein.

BACKGROUND: Circulating levels of the systemic inflammation marker C-reactive protein (CRP) have been associated with increased risk and poor outcomes of many diseases, such as cardiovascular events and cancer. Accumulating evidence has indicated that the conformational rearrangement of human pentameric CRP (pCRP) to monomeric CRP (mCRP) is a prerequisite for participation in the pathogenesis. Therefore, determining the mechanism of the dissociation of pCRP into pro-inflammatory mCRP under physiological/pathological circumstances has been intriguing. METHODS: The effects of oxidative and acidic stress occurring in inflammation on pCRP were examined by electrophoresis, electron microscopy, protein fluorescence, neoepitope expression and endothelial cell responses. RESULTS: Reactive oxygen species (ROS) generated by the copper-hydrogen peroxide system could rapidly induce the dissociation of CRP at mild acidic pH within four hours, but not at physiological pH of 7.4. Meanwhile, mannitol, a ROS scavenger, could not protect against dissociation, which implied that local ROS from accessible histidine residues may be crucially beneficial to the formation of mCRP in a redox-balanced microenvironment. Furthermore, mCRP generated by ROS could be reduced by DTT, which indicated the exposure of functional motif aa35-47, and showed potent proinflammatory actions on endothelial cells, comparable to mCRP generated by urea. CONCLUSION: dissociation of pCRP to mCRP could be rapidly induced by ROS from copper- hydrogen peroxide system in dependence on mildly acidic stress regardless of a redox-balanced microenvironment.

Evaluation of TCR Vbeta subfamily T cell expansion in NOD/SCID mice transplanted with human cord blood hematopoietic stem cells.

Examination of the T cell receptor (TCR) gene repertoire is important in the analysis of the immune status of models, because clonal expansion of T cells permits the identification of specific antigen responses of T cells. Little is known about T-cell immunity in the humanized NOD/SCID mouse model. TCR Vbeta repertoire usage and clonality were analyzed to investigate the distribution and clonal expansion of TCR Vbeta subfamily T cells in NOD/SCID mice transplanted with human cord blood (CB) hematopoietic stem cells. The NOD/SCID mice were sublethally irradiated ((60)Co, 300cGy) to eliminate residual innate immunity in the host. The experimental mice were transplanted intravenously with CB CD34(+) cells sorted by MACS. After 6 weeks, RNA was obtained from peripheral blood, bone marrow and thymus of the study animals. The gene expression and clonality of the TCR Vbeta repertoire were determined by RT-PCR and GeneScan techniques. A restricted range of TCR Vbeta usage was exhibited in the bone marrow of mice, which included TCR Vbeta 1, 2, 9, 13 and 19. Further, oligoclonal expression of some TCR Vbeta subfamilies (Vbeta9, 13, 19) was identified by GeneScan technique. To investigate the reason for oligoclonal expansion of the TCR Vbeta subfamily T cells from CB in mouse models, the T-cell culture with tissue-antigen of NOD/SCID mouse was performed in vitro. The cells from peripheral blood mononuclear cells and bone marrow, spleen, thymus in NOD/SCID mice were frozen and thawed, and used as tissue-antigen. CB mononuclear cells were separately cultured with the component from those murine cells for 15-20 days. Oligoclonal expression or oligoclonal trend of some TCR Vbeta subfamilies (Vbeta10, 11 and Vbeta2, 15, 16, 19) was detected in T cells after stimulation with tissue-antigen of NOD/SCID mouse. Interestingly, a similar clonal expansion of the TCR Vbeta11 subfamily was found in T cells cultured with peripheral blood, bone marrow and spleen respectively. The TCR Vbeta subfamily T cells could be reconstituted in humanized NOD/SCID mouse transplanted with CD34(+) cells from CB. The restricted expression and clonal expansion of some CB T cell clones may be induced by tissue-antigens of NOD/SCID mice.