Differences in Prevalence of Histologic Gastric Cancer Subtypes Between Mestizo and Mayan Populations in Guatemala.

PURPOSE: Although the intestinal subtype of gastric cancer (GC) is most prevalent around the world, a relatively high prevalence of the diffuse subtype has been reported in some populations of Central American countries, including Guatemala. This study aimed to investigate whether differences exist in the prevalence of the two GC subtypes in the two main ethnic groups in Guatemala, namely Mayan and Mestizo (known as Ladino in Guatemala), between whom significant socioeconomic disparities exist, and to determine whether there is an association with Helicobacter pylori/CagA seropositivity. MATERIALS AND METHODS: Participants included 65 patients with GC and 135 age-/sex-matched controls. Data on ethnicity, H. pylori and CagA seropositivity status, as well as tumor subtype (diffuse or intestinal) were collected. Logistic regression models were fitted to examine the relationship between predictor variables (age, sex, ethnicity, H. pylori, and CagA) and the binary response variable (tumor type). Model selection was based on the Akaike information criterion. RESULTS: The prevalence of diffuse GC was found to be significantly higher in the Mayan compared with the Mestizo population in Guatemala. Although seropositivity for CagA was significantly higher in patients with GC, there were no significant differences between the two GC subtypes. CONCLUSION: This study suggests that there are differences in the prevalence of intestinal and diffuse GC histologic subtypes between the two main ethnic groups in Guatemala. Further studies are warranted, given the potential higher prevalence of the more severe GC subtype in the most vulnerable population.

The role of gastric electrical stimulation in postsurgical gastroparesis: a retrospective analysis from 2 centers.

BACKGROUND: Postsurgical gastroparesis, resulting from surgical interventions on the stomach or vagal nerve injury, poses significant clinical challenges with patients presenting symptoms such as nausea, vomiting, and abdominal pain. Although gastric electrical stimulation (GES) offers potential relief, its efficacy in refractory postsurgical gastroparesis requires further examination. This study evaluated the clinical response to GES in patients with refractory postsurgical gastroparesis. METHODS: A retrospective study was conducted across 2 study sites, involving 185 patients with drug-refractory postsurgical gastroparesis who underwent both temporary and permanent GES placements. Patients were categorized based on their surgical history: bariatric surgery, Nissen fundoplication, and others. The impact of GES was evaluated using Food and Drug Administration-compliant patient-reported outcomes scores and other relevant clinical metrics at baseline, after temporary GES placement, and 6 months after permanent GES placement. All 3 groups were also analyzed by the symptom improved group vs the unimproved group at baseline and 6 months after GES placement. RESULTS: After GES implantation, all patient groups significantly improved upper gastrointestinal symptoms. The bariatric surgery group and Nissen fundoplication group specifically identified anorexia as the most severe symptom after GES after temporary GES placement among 3 groups (2.5 [0.4-3.5] and 1.5 [0.0-2.5], respectively). Nissen fundoplication patients had the highest score of anorexia among the 3 groups 6 months after GES (3.0 [2.0-3.5], P = .018). Despite these improvements, GES did not enhance gastric emptying test results. Symptomatic improvements were notably significant in patients who initially reported higher symptom severity than those who did not. CONCLUSION: GES shows promise in alleviating symptoms of refractory postsurgical gastroparesis, particularly in those with severe initial symptoms. However, its impact on gastric emptying remains inconclusive. Further research is needed to establish GES as a standard treatment for postsurgical gastroparesis.

Autonomic and Enteric Profiling May Help Predict Response to Diverse Obesity Therapies.

PURPOSE: Changes in autonomic (ANS) and enteric nervous systems (ENS) may be involved in pathogenesis of obesity. We hypothesized that baseline autonomic and enteric parameters may predict outcomes of diverse obesity therapies. MATERIAL AND METHODS: We studied ANS and ENS physiology in 37 patients (8 male, 29 female, age 45 years, weight 129.7 kg) at 4 centers in patients undergoing medical (9: low-calorie diet) versus invasive (22: 16 sleeve, 6 bypass) and semi-invasive (6: 2 band, 2 high energy stimulation, 2 aspiration) weight loss therapies. Weight loss was reported as percent weight loss from baseline to latest values at 1 year and in some up to 5 years; classified as < or > /= 20% for each group. ANS testing included sympathetic adrenergic function by measuring reflex vasoconstriction and postural adjustment ratio. ENS was measured non-invasively using cutaneous low-resolution electrogastrogram. RESULTS: Percent weight loss was greater with the invasive (28.5%) than semi-invasive (9.1%) or non-invasive low-calorie diet (4.4%) (p < .001). Percent weight loss at 1 year (and up to 5 years) corresponded to the adrenergic measure of postural adjustment ratio (r = .42, p = .012), total pulse amplitude at rest (r = .56, p < .001), and electrogastrogram standing-to-rest difference (r = .33, p = .056). CONCLUSION: Baseline autonomic and enteric function measures correspond to percentage with loss in this pilot study using diverse weight loss methods. Autonomic and enteric profiling has potential clinical use for evaluation and treatment of obesity but needed larger controlled trials.

Frameless image-guided linear accelerator (LINAC) stereotactic radiosurgery for medically refractory trigeminal neuralgia: Clinical outcomes in 116 patients.

Background: Frameless image-guided radiosurgery (IGRS) is an effective and non-invasive method of treating patients who are unresponsive to medical management for trigeminal neuralgia (TN). This study evaluated the use of frameless IGRS to treat patients with medically refractory TN. Methods: We performed a retrospective review of records of 116 patients diagnosed with TN who underwent frameless IGRS using a linear accelerator (LINAC) over 10 years (March 2012-February 2023). All patients had failed medical management for TN. Facial pain was graded using the Barrow Neurological Institute (BNI) scoring system. Each patient received a BNI score before frameless IGRS and following treatment. Failure was defined as a BNI score IV-V at the last follow-up and/or undergoing a salvage procedure following IGRS. Results: All patients had a BNI score of either IV or V before the frameless IGRS. The mean follow-up duration for all 116 patients following IGRS was 44.1 months. Most patients (81 [69.8%]) had not undergone surgery (microvascular decompression [MVD] or rhizotomy) or stereotactic radiosurgery (SRS) for TN before frameless IGRS. A total of 41 (35.3%) patients underwent a salvage procedure (MVD, rhizotomy, or an additional IGRS) following frameless IGRS. The mean duration between the initial frameless IGRS and salvage procedure was 20.1 months. At the last follow-up, a total of 110 (94.8%) patients had a BNI score of I-III. No complications were reported after the frameless IGRS. The BNI score at the last follow-up was lower compared to the initial BNI for patients regardless of prior intervention (P < 0.001). Patients who failed IGRS had a higher BNI score at the last follow-up compared to those who did not fail IGRS (2.8 vs. 2.5, P = 0.05). Patients with pain relief had a shorter follow-up compared to those with pain refractory to SRS (38.0 vs. 55.1, P = 0.005). Conclusion: In this large cohort of patients with medically refractory TN, frameless IGRS resulted in durable pain control in the majority of patients without any toxicity.

Impact of Reirradiation Utilizing Fractionated Stereotactic Radiotherapy for Recurrent Glioblastoma.

BACKGROUND: Patients with recurrent glioblastoma (GBM) have limited treatment options. This study determined whether patients with recurrent GBM treated with initial radiation/temozolomide (TMZ) and reirradiation using fractionated stereotactic radiotherapy (FSRT) had improved outcomes. MATERIALS AND METHODS: We identified 95 patients with recurrent GBM, 50 of whom underwent FSRT at recurrence and 45 who had systemic treatment only (control). The median total FSRT dose at the time of GBM recurrence was 30 Gy in five fractions of the gadolinium-enhanced tumor only. RESULTS: With a median follow-up of 18 months, the progression-free survival (PFS) and overall survival (OS) following initial GBM diagnosis were longer in the reirradiation group compared to the control group (13.5 vs. 7.5 months [p=0.001] and 24.6 vs. 12.6 months [p<0.001], respectively). For patients who underwent reirradiation, the median time interval between the end of the initial radiation and reirradiation was 15.2 months. The median OS after GBM recurrence was longer in the reirradiation group versus the control group (9.9 vs. 3.5 months [p<0.001]), with a one-year OS survival rate of 22%. The hazard ratio for death of patients in the reirradiation group was 0.31 [0.19-0.50]. The reirradiation group had a higher percentage of patients who received bevacizumab (BEV, 62.0% vs. 28.9%, p=0.002) and a lower percentage of patients whose TMZ was discontinued due to toxicity (8.0% vs. 28.9%, p=0.017) compared to the control group. CONCLUSIONS: Reirradiation utilizing FSRT was associated with improved PFS and OS after GBM recurrence compared to the control group who did not receive additional irradiation.

Cystatin F (Cst7) drives sex-dependent changes in microglia in an amyloid-driven model of Alzheimer's disease.

Microglial endolysosomal (dys)function is strongly implicated in neurodegenerative disease. Transcriptomic studies show that a microglial state characterised by a set of genes involved in endolysosomal function is induced in both mouse Alzheimer's disease (AD) models and human AD brain, and that the emergence of this state is emphasised in females. Cst7 (encoding cystatin F) is among the most highly upregulated genes in these microglia. However, despite such striking and robust upregulation, the function of Cst7 in neurodegenerative disease is not understood. Here, we crossed Cst7-/- mice with the AppNL-G-F mouse to test the role of Cst7 in a model of amyloid-driven AD. Surprisingly, we found that Cst7 plays a sexually dimorphic role regulating microglia in this model. In females, Cst7-/-AppNL-G-F microglia had greater endolysosomal gene expression, lysosomal burden, and amyloid beta (Aß) burden in vivo and were more phagocytic in vitro. However, in males, Cst7-/-AppNL-G-F microglia were less inflammatory and had a reduction in lysosomal burden but had no change in Aß burden. Overall, our study reveals functional roles for one of the most commonly upregulated genes in microglia across disease models, and the sex-specific profiles of Cst7-/--altered microglial disease phenotypes. More broadly, the findings raise important implications for AD including crucial questions on sexual dimorphism in neurodegenerative disease and the interplay between endolysosomal and inflammatory pathways in AD pathology.

ß-Cryptoxanthin Attenuates Cigarette-Smoke-Induced Lung Lesions in the Absence of Carotenoid Cleavage Enzymes (BCO1/BCO2) in Mice.

High dietary intake of ß-cryptoxanthin (BCX, an oxygenated provitamin A carotenoid) is associated with a lower risk of lung disease in smokers. BCX can be cleaved by ß-carotene-15,15'-oxygenase (BCO1) and ß-carotene-9',10'-oxygenase (BCO2) to produce retinol and apo-10'-carotenoids. We investigated whether BCX has protective effects against cigarette smoke (CS)-induced lung injury, dependent or independent of BCO1/BCO2 and their metabolites. Both BCO1-/-/BCO2-/- double knockout mice (DKO) and wild type (WT) littermates were supplemented with BCX 14 days and then exposed to CS for an additional 14 days. CS exposure significantly induced macrophage and neutrophil infiltration in the lung tissues of mice, regardless of genotypes, compared to the non-exposed littermates. BCX treatment significantly inhibited CS-induced inflammatory cell infiltration, hyperplasia in the bronchial epithelium, and enlarged alveolar airspaces in both WT and DKO mice, regardless of sex. The protective effects of BCX were associated with lower expression of IL-6, TNF-α, and matrix metalloproteinases-2 and -9. BCX treatment led to a significant increase in hepatic BCX levels in DKO mice, but not in WT mice, which had significant increase in hepatic retinol concentration. No apo-10'-carotenoids were detected in any of the groups. In vitro BCX, at comparable doses of 3-OH-ß-apo-10'-carotenal, was effective at inhibiting the lipopolysaccharide-induced inflammatory response in a human bronchial epithelial cell line. These data indicate that BCX can serve as an effective protective agent against CS-induced lung lesions in the absence of carotenoid cleavage enzymes.

Flexible evaluation of surrogacy in platform studies.

Trial-level surrogates are useful tools for improving the speed and cost effectiveness of trials but surrogates that have not been properly evaluated can cause misleading results. The evaluation procedure is often contextual and depends on the type of trial setting. There have been many proposed methods for trial-level surrogate evaluation, but none, to our knowledge, for the specific setting of platform studies. As platform studies are becoming more popular, methods for surrogate evaluation using them are needed. These studies also offer a rich data resource for surrogate evaluation that would not normally be possible. However, they also offer a set of statistical issues including heterogeneity of the study population, treatments, implementation, and even potentially the quality of the surrogate. We propose the use of a hierarchical Bayesian semiparametric model for the evaluation of potential surrogates using nonparametric priors for the distribution of true effects based on Dirichlet process mixtures. The motivation for this approach is to flexibly model relationships between the treatment effect on the surrogate and the treatment effect on the outcome and also to identify potential clusters with differential surrogate value in a data-driven manner so that treatment effects on the surrogate can be used to reliably predict treatment effects on the clinical outcome. In simulations, we find that our proposed method is superior to a simple, but fairly standard, hierarchical Bayesian method. We demonstrate how our method can be used in a simulated illustrative example (based on the ProBio trial), in which we are able to identify clusters where the surrogate is, and is not useful. We plan to apply our method to the ProBio trial, once it is completed.

Random forest modelling demonstrates microglial and protein misfolding features to be key phenotypic markers in C9orf72-ALS.

Clinical heterogeneity observed across patients with amyotrophic lateral sclerosis (ALS) is a known complicating factor in identifying potential therapeutics, even within cohorts with the same mutation, such as C9orf72 hexanucleotide repeat expansions (HREs). Thus, further understanding of pathways underlying this heterogeneity is essential for appropriate ALS trial stratification and the meaningful assessment of clinical outcomes. It has been shown that both inflammation and protein misfolding can influence ALS pathogenesis, such as the manifestation or severity of motor or cognitive symptoms. However, there has yet to be a systematic and quantitative assessment of immunohistochemical markers to interrogate the potential relevance of these pathways in an unbiased manner. To investigate this, we extensively characterised features of commonly used glial activation and protein misfolding stains in thousands of images of post-mortem tissue from a heterogeneous cohort of deeply clinically profiled patients with a C9orf72 HRE. Using a random forest model, we show that microglial staining features are the most accurate classifiers of disease status in our panel and that clinicopathological relationships exist between microglial activation status, TDP-43 pathology, and language dysfunction. Furthermore, we detected spatially resolved changes in fused in sarcoma (FUS) staining, suggesting that liquid-liquid phase shift of this aggregation-prone RNA-binding protein may be important in ALS caused by a C9orf72 HRE. Interestingly, no one feature alone significantly impacted the predictiveness of the model, indicating that the collective examination of all features, or a combination of several features, is what allows the model to be predictive. Our findings provide further support to the hypothesis of dysfunctional immune regulation and proteostasis in the pathogenesis of C9-ALS and provide a framework for digital analysis of commonly used neuropathological stains as a tool to enrich our understanding of clinicopathological relationships within and between cohorts. © 2022 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.

Treatment with IgM-enriched intravenous immunoglobulins enhances clearance of stroke-associated bacterial lung infection.

Post-stroke infection is a common complication of stroke that is associated with poor outcome. We previously reported that stroke induces an ablation of multiple sub-populations of B cells and reduces levels of immunoglobulin M (IgM) antibody, which coincides with the development of spontaneous bacterial pneumonia. The loss of IgM after stroke could be an important determinant of infection susceptibility and highlights this pathway as a target for intervention. We treated mice with a replacement dose of IgM-enriched intravenous immunoglobulin (IgM-IVIg) prior to and 24 h after middle cerebral artery occlusion (MCAO) and allowed them to recover for 2- or 5-day post-surgery. Treatment with IgM-IVIg enhanced bacterial clearance from the lung after MCAO and improved lung pathology but did not impact brain infarct volume. IgM-IVIg treatment induced immunomodulatory effects systemically, including rescue of splenic plasma B cell numbers and endogenous mouse IgM and IgA circulating immunoglobulin concentrations that were reduced by MCAO. Treatment attenuated MCAO-induced elevation of selected pro-inflammatory cytokines in the lung. IgM-IVIg treatment did not increase the number of lung mononuclear phagocytes or directly modulate macrophage phagocytic capacity but enhanced phagocytosis of Staphylococcus aureus bioparticles in vitro. Low-dose IgM-IVIg contributes to increased clearance of spontaneous lung bacteria after MCAO likely via increasing availability of antibody in the lung to enhance opsonophagocytic activity. Immunomodulatory effects of IgM-IVIg treatment may also contribute to reduced levels of damage in the lung after MCAO. IgM-IVIg shows promise as an antibacterial and immunomodulatory agent to use in the treatment of post-stroke infection.

Impact of Distance From the Hospital and Patient Transfer on Pediatric Testicular Torsion Outcomes.

BACKGROUND: Testicular torsion is the most common pediatric emergency that requires prompt diagnosis and surgical treatment to prevent testicular loss. Distance from the hospital where the patient will be undergoing treatment for testicular torsion and transfer from an outside facility are factors that may impact whether a testis is salvageable. We sought to determine whether these factors play a role in pediatric testicular torsion outcomes.  Materials and Methods: We identified males aged 1-18 years with testicular torsion between January 1, 2015 and December 31, 2020. The patients' distance from our hospital and whether they were transferred from an outlying hospital were a particular focus.  Results: The number of miles from our hospital and transfer from an outlying hospital were not significantly different between boys who underwent an orchiectomy versus an orchiopexy (p=0.258 and p=0.574, respectively). The number of miles from our hospital was negatively correlated to age at surgery (rho=-0.22, p=0.01). Significantly (p<0.001) more transfers were seen in patients who lived far (>22.1 miles) from our hospital (32/69 (46%)) versus near our hospital (10/68 (15%)). For every mile boys lived from our hospital, there was no difference (adjusted odds ratio (OR)=0.98 (0.96, 1.00), p=0.10) in the likelihood of receiving an orchiectomy versus an orchiopexy when adjusting for age, symptom duration, and degrees of torsion. CONCLUSIONS: Our study determined that neither distance from our hospital nor transfer from an outlying hospital affected the orchiectomy rate. An expedited medical evaluation and surgery offer the best prognosis for salvaging the testes.

Sonography Findings Predict Testicular Viability in Pediatric Patients With Testicular Torsion.

BACKGROUND: Testicular torsion poses a pediatric surgical emergency that necessitates rapid diagnosis and surgery to prevent testicular loss. We sought to determine whether any particular findings on Doppler ultrasound (US) were predictive of testicular viability in pediatric patients with testicular torsion. MATERIALS AND METHODS: We identified males between ages one and 18 years who experienced testicular torsion over a six-year period (January 1, 2015-December 31, 2020). All patients were evaluated at our institution's emergency department by a pediatric urologist and underwent a Doppler scrotal US. RESULTS: Of the 140 patients with testicular torsion, 56 (40%) had a non-viable testis and underwent an orchiectomy, while 84 (60%) had a viable testis and orchiopexy. Testicular heterogeneity (47 [84%] vs 48 [57%], p = 0.001), epididymis heterogeneity (23 [41%] vs 21 [25%], p = 0.063), and scrotal wall thickening (25 [45%] vs 5 [6%], p < 0.001) were significantly associated with a non-viable testis. Epididymis heterogeneity (adj. odds ratio [OR] = 0.33 [0.13, 0.79], p = 0.013) and scrotal wall thickening (adj. OR = 0.08 [0.03, 0.24], p < 0.001) exhibited significantly lower odds for viability. Testicular heterogeneity and scrotal wall thickening were more likely to develop with a longer duration of symptoms (both p < 0.001). CONCLUSION: Our study determined that certain Doppler scrotal US findings, specifically, testicular and epididymal heterogeneity as well as a thickened scrotal wall, are associated with testicular demise in patients with testicular torsion. As testicular heterogeneity and scrotal wall thickening are more likely to arise with a longer symptom duration, an urgent diagnosis and prompt surgical intervention are imperative to avert testicular loss.

Surge in testicular torsion in pediatric patients during the COVID-19 pandemic.

BACKGROUND: Testicular torsion is a pediatric surgical emergency, and prompt diagnosis and treatment is imperative. During the COVID-19 pandemic, pediatric patients with symptoms of testicular torsion may be reluctant to seek medical care which increases the likelihood of delayed presentation and the need for an orchiectomy. This observational study sought to determine whether there was a higher number of testicular torsion cases during COVID-19. METHODS: As the first patient with COVID-19 was admitted to our facility on March 6, 2020, we identified male children ages 1-18 years with testicular torsion between March 1-December 31, 2020 (during COVID-19) compared to the same time period between 2015 and 2019 (prior to COVID-19). All patients were evaluated at our Institution's Emergency Department by a pediatric urologist. RESULTS: There were 38 cases of testicular torsion between March 1-December 31, 2020 compared to 15.8 cases on average during the same 10-month period between 2015 and 2019 (a total of 79 cases). There was a statistically significant increase in testicular torsion cases during the COVID-19 pandemic compared to equivalent time periods in 2015-2019 (38 vs. 15.8, p = 0.05). Patients with testicular torsion during the COVID-19 pandemic were younger, had a longer duration of symptoms, and had a higher number of orchiectomies (although not statistically significant). CONCLUSION: During the COVID-19 pandemic, an escalation in testicular torsion cases was observed. Timely assessment, diagnosis, and surgery are crucial to prevent testicular loss and potential infertility in the future. Further evaluation is needed to elucidate the surge in testicular torsion and possible mechanisms.

A Bayesian nonparametric approach for evaluating the causal effect of treatment in randomized trials with semi-competing risks.

We develop a Bayesian nonparametric (BNP) approach to evaluate the causal effect of treatment in a randomized trial where a nonterminal event may be censored by a terminal event, but not vice versa (i.e., semi-competing risks). Based on the idea of principal stratification, we define a novel estimand for the causal effect of treatment on the nonterminal event. We introduce identification assumptions, indexed by a sensitivity parameter, and show how to draw inference using our BNP approach. We conduct simulation studies and illustrate our methodology using data from a brain cancer trial. The R code implementing our model and algorithm is available for download at https://github.com/YanxunXu/BaySemiCompeting.

Adjusting for selection bias due to missing data in electronic health records-based research.

While electronic health records data provide unique opportunities for research, numerous methodological issues must be considered. Among these, selection bias due to incomplete/missing data has received far less attention than other issues. Unfortunately, standard missing data approaches (e.g. inverse-probability weighting and multiple imputation) generally fail to acknowledge the complex interplay of heterogeneous decisions made by patients, providers, and health systems that govern whether specific data elements in the electronic health records are observed. This, in turn, renders the missing-at-random assumption difficult to believe in standard approaches. In the clinical literature, the collection of decisions that gives rise to the observed data is referred to as the data provenance. Building on a recently-proposed framework for modularizing the data provenance, we develop a general and scalable framework for estimation and inference with respect to regression models based on inverse-probability weighting that allows for a hierarchy of missingness mechanisms to better align with the complex nature of electronic health records data. We show that the proposed estimator is consistent and asymptotically Normal, derive the form of the asymptotic variance, and propose two consistent estimators. Simulations show that naïve application of standard methods may yield biased point estimates, that the proposed estimators have good small-sample properties, and that researchers may have to contend with a bias-variance trade-off as they consider how to handle missing data. The proposed methods are motivated by an on-going, electronic health records-based study of bariatric surgery.

Thromboembolic events in metastatic testicular cancer treated with cisplatin-based chemotherapy.

BACKGROUND: Testicular germ cell tumor (TGCT) is the most curable solid tumor and most common cancer among men 18-39 years. While cisplatin-based chemotherapy has significantly lengthened the survival of patients with TGCT, it is associated with a high rate of thromboembolic events (TEE). AIM: To summarize our single-center experience highlighting patients who were diagnosed with TGCT and received platinum-based chemotherapy, with special attention to those patients who suffered a TEE. METHODS: A retrospective analysis of the medical records and imaging studies of 68 consecutive individuals who were diagnosed with TGCT and received platinum-based chemotherapy at our Institution in a metropolitan community between January 1, 2014 and December 31, 2019. RESULTS: A total of 19 (28%) patients experienced a TEE following orchiectomy which occurred during chemotherapy in 13 (68%) of these patients. Patients with a higher pathologic stage (stage III) were significantly (P = 0.023) more likely to experience a TEE compared to patients who had a lower stage. Additionally, patients who were treated with 3 cycles of bleomycine, etoposide, and cisplatin and 1 cycle of etoposide and cisplatin or 4 cycles of etoposide and cisplatin were significantly 5 (P = 0.02) times more likely to experience a TEE compared to patients who were treated with only 3 cycles of bleomycine, etoposide, and cisplatin. CONCLUSION: Due to numerous factors that predispose to a TEE such as large retroperitoneal disease, higher clinical stage, greater number of chemotherapy cycle, central venous catheter, cigarette smoking, and possible cannabis use, high-risk ambulatory patients with TGCT treated with cisplatin-based chemotherapy may benefit from prophylactic anticoagulation. Randomized studies to evaluate the safety and efficacy of prophylactic anticoagulants are warranted in this young patient population generally devoid of medical co-morbidities.

Protocol-driven prevention of perioperative hypothermia in the pediatric neurosurgical population.

OBJECTIVE: Perioperative hypothermia (PH) is a preventable, pathological, and iatrogenic state that has been shown to result in increased surgical blood loss, increased surgical site infections, increased hospital length of stay, and patient discomfort. Maintenance of normothermia is recommended by multiple surgical quality organizations; however, no group yet provides an ergonomic, evidence-based protocol to reduce PH for pediatric neurosurgery patients. The authors' aim was to evaluate the efficacy of a PH prevention protocol in the pediatric neurosurgery population. METHODS: A prospective, nonrandomized study of 120 pediatric neurosurgery patients was performed. Thirty-eight patients received targeted warming interventions throughout their perioperative phases of care (warming group-WG). The remaining 82 patients received no extra warming care during their perioperative period (control group-CG). Patients were well matched for age, sex, and preparation time intraoperatively. Hypothermia was defined as < 36°C. The primary outcome of the study was maintenance of normothermia preoperatively, intraoperatively, and postoperatively. RESULTS: WG patients were significantly warmer on arrival to the operating room (OR) and were 60% less likely to develop PH (p < 0.001). Preoperative forced air warmer use both reduced the risk of PH at time 0 intraoperatively and significantly reduced the risk of any PH intraoperatively (p < 0.001). All patients, regardless of group, experienced a drop in core temperature until a nadir occurred at 30 minutes intraoperatively for the WG and 45 minutes for the CG. At every time interval, from preoperatively to 120 minutes intraoperatively, CG patients were between 2 and 3 times more likely to experience PH (p < 0.001). All patients were warm on arrival to the postanesthesia care unit regardless of patient group. CONCLUSIONS: Preoperative forced air warmer use significantly increases the average intraoperative time 0 temperature, helping to prevent a fall into PH at the intraoperative nadir. Intraoperatively, a strictly and consistently applied warming protocol made intraoperative hypothermia significantly less likely as well as less severe when it did occur. Implementation of a warming protocol necessitated only limited resources and an OR culture change, and was well tolerated by OR staff.

Relationships of protein biomarkers of the urokinase plasminogen activator system with expression of their cognate genes in primary breast carcinomas.

BACKGROUND: uPA, its receptor uPAR, and inhibitors PAI-1 and PAI-2 play key roles in membrane remodeling/invasion and in predicting response to chemotherapy. We identified novel relationships of these biomarkers with ER/PR that indicate clinical utility for assessing breast carcinoma outcomes. METHODS: Retrospective studies were performed with de-identified results of (a) uPA, uPAR, and PAI-1; (b) estrogen (ER) and progestin receptor (PR); and (c) clinical outcomes. Relative expression of 22 000 genes from microarray of RNA from LCM-procured breast cancer cells was used with R Studio version 3.4.1. RESULTS: Primary ER/PR status was related to uPA, uPAR, or PAI-1 levels. ER- or PR- cancers expressed elevated uPA, uPAR, and PAI2 mRNA compared to ER+ or PR+ cells. Inverse relationships between ER/PR protein and expression of uPA, uPAR, and PAI-2 were observed, whereas HER2 status was unrelated. qPCR analyses showed RERG and NQO-1 expressions were elevated in uPA- lesions, while CD34 and EDG-1 were elevated in uPAR- cancers. ERBB4 was overexpressed in PAI-1+ carcinomas. Cox regression analyses revealed relationships of ER/PR status and uPA system members with regard to clinical outcomes of breast cancer. CONCLUSIONS: uPA, uPAR, PAI1, or PAI2 expression was increased in either ER- or PR- cancers similar to that of protein content in ER-/PR- carcinomas, suggesting sex hormones regulate the uPA system in breast cancer. Results revealed protein content of uPA system members was related to ER/PR status of primary lesions. Use of LCM-procured carcinoma cells uncovered relationships between expression of known cancer-associated genes and protein content of uPA system members. Collectively, results indicate evaluation of ER and PR protein of primary breast cancers combined with analyses of uPA, uPAR, and PAI-1 protein content improves assessment of clinical outcomes.

The three cytokines IL-1ß, IL-18, and IL-1α share related but distinct secretory routes.

Interleukin (IL)-1 family cytokines potently regulate inflammation, with the majority of the IL-1 family proteins being secreted from immune cells via unconventional pathways. In many cases, secretion of IL-1 cytokines appears to be closely coupled to cell death, yet the secretory mechanisms involved remain poorly understood. Here, we studied the secretion of the three best-characterized members of the IL-1 superfamily, IL-1α, IL-1ß, and IL-18, in a range of conditions and cell types, including murine bone marrow-derived and peritoneal macrophages, human monocyte-derived macrophages, HeLa cells, and mouse embryonic fibroblasts. We discovered that IL-1ß and IL-18 share a common secretory pathway that depends upon membrane permeability and can operate in the absence of complete cell lysis and cell death. We also found that the pathway regulating the trafficking of IL-1α is distinct from the pathway regulating IL-1ß and IL-18. Although the release of IL-1α could also be dissociated from cell death, it was independent of the effects of the membrane-stabilizing agent punicalagin, which inhibited both IL-1ß and IL-18 release. These results reveal that in addition to their role as danger signals released from dead cells, IL-1 family cytokines can be secreted in the absence of cell death. We propose that models used in the study of IL-1 release should be considered context-dependently.

Urea Cycle Sustains Cellular Energetics upon EGFR Inhibition in EGFR-Mutant NSCLC.

Mutations in oncogenes and tumor suppressor genes engender unique metabolic phenotypes crucial to the survival of tumor cells. EGFR signaling has been linked to the rewiring of tumor metabolism in non-small cell lung cancer (NSCLC). We have integrated the use of a functional genomics screen and metabolomics to identify metabolic vulnerabilities induced by EGFR inhibition. These studies reveal that following EGFR inhibition, EGFR-driven NSCLC cells become dependent on the urea cycle and, in particular, the urea cycle enzyme CPS1. Combining knockdown of CPS1 with EGFR inhibition further reduces cell proliferation and impedes cell-cycle progression. Profiling of the metabolome demonstrates that suppression of CPS1 potentiates the effects of EGFR inhibition on central carbon metabolism, pyrimidine biosynthesis, and arginine metabolism, coinciding with reduced glycolysis and mitochondrial respiration. We show that EGFR inhibition and CPS1 knockdown lead to a decrease in arginine levels and pyrimidine derivatives, and the addition of exogenous pyrimidines partially rescues the impairment in cell growth. Finally, we show that high expression of CPS1 in lung adenocarcinomas correlated with worse patient prognosis in publicly available databases. These data collectively reveal that NSCLC cells have a greater dependency on the urea cycle to sustain central carbon metabolism, pyrimidine biosynthesis, and arginine metabolism to meet cellular energetics upon inhibition of EGFR. IMPLICATIONS: Our results reveal that the urea cycle may be a novel metabolic vulnerability in the context of EGFR inhibition, providing an opportunity to develop rational combination therapies with EGFR inhibitors for the treatment of EGFR-driven NSCLC.