15-Lipoxygenase-Mediated Lipid Peroxidation Regulates LRRK2 Kinase Activity.

Mutations in leucine-rich repeat kinase 2 (LRRK2) that increase its kinase activity are strongly linked to genetic forms of Parkinson's disease (PD). However, the regulation of endogenous wild-type (WT) LRRK2 kinase activity remains poorly understood, despite its frequent elevation in idiopathic PD (iPD) patients. Various stressors such as mitochondrial dysfunction, lysosomal dyshomeostasis, or vesicle trafficking deficits can activate WT LRRK2 kinase, but the specific molecular mechanisms are not fully understood. We found that the production of 4-hydroxynonenal (4-HNE), a lipid hydroperoxidation end-product, is a common biochemical response to these diverse stimuli. 4-HNE forms post-translational adducts with Cys2024 and Cys2025 in the kinase activation loop of WT LRRK2, significantly increasing its kinase activity. Additionally, we discovered that the 4-HNE responsible for regulating LRRK2 is generated by the action of 15-lipoxygenase (15-LO), making 15-LO an upstream regulator of the pathogenic hyperactivation of LRRK2 kinase activity. Pharmacological inhibition or genetic ablation of 15-LO prevents 4-HNE post-translational modification of LRRK2 kinase and its subsequent pathogenic hyperactivation. Therefore, 15-LO inhibitors, or methods to lower 4-HNE levels, or the targeting of Cys2024/2025 could provide new therapeutic strategies to modulate LRRK2 kinase activity and treat PD.

Does Fixation of the Gastric Conduit Reduce the Incidence of Gastric Volvulus After Esophagectomy?

BACKGROUND: Acute volvulus of the gastric conduit is a rare complication after esophagectomy that warrants surgical intervention and is associated with increased morbidity and mortality. The aim of the study is to evaluate whether fixation of the gastric conduit would reduce the incidence of postoperative volvulus following esophagectomy. METHODS: This single-center retrospective analysis of patients who underwent esophagectomy was conducted to determine the incidence of acute postoperative volvulus following a change in practice. All patients who underwent an esophagectomy from September 2013 to November 2022 were included. We compared postoperative outcomes of gastric conduit volvulus, reoperations, morbidity, and mortality among those who had fixation versus non-fixation of the conduit to the right pleural edge. RESULTS: Two hundred and forty-two consecutive patients underwent minimally invasive esophagectomy (81% male, 41% were < 67 years old). The first 121 (50%) patients did not undergo fixation of the gastric conduit, while the subsequent 121 (50%) patients did undergo fixation. Comparing both groups, there were no significant differences in major complications, anastomotic leak, and 30-day and 90-day all-cause mortality. Four (2%) patients developed gastric conduit volvulus in the non-fixation group, requiring reoperative intervention. Following implementation of fixation, no patient experienced gastric volvulus. CONCLUSION: Acute volvulus of the gastric conduit is a rare complication after esophagectomy. Early diagnosis and surgical intervention are critical. In this study, although not statistically significant, fixation of the gastric conduit did reduce the number of patients who experienced postoperative volvulus. Additional future studies are needed to validate this technique and the prevention of postoperative acute gastric conduit volvulus among a diverse patient population.

Tumor differentiation impacts response to neoadjuvant therapy and survival in patients with esophageal adenocarcinoma.

OBJECTIVE: The current staging system for esophageal adenocarcinoma only considers tumor grade in early tumors. The aim of this study was to evaluate the impact of tumor differentiation on response to neoadjuvant chemoradiotherapy and survival in patients with locally advanced esophageal adenocarcinoma. METHODS: This was a multi-institution retrospective review of all patients with esophageal cancer who underwent neoadjuvant chemoradiotherapy followed by esophagectomy from January 2010 to December 2017. Response to neoadjuvant therapy and survival was compared between patients with well- or moderately differentiated (G1/2) tumors versus poorly differentiated (G3) tumors. RESULTS: There were 550 patients, 485 men (88.2%) and 65 women. The median age was 61 years, and the tumor was G1/2 in 288 (52.4%) and G3 in 262 patients. Overall clinical stage before neoadjuvant therapy was similar between groups. Pathologic complete response (pCR) was found in 87 patients (15.8%). The frequency of pCR was similar between groups, but residual disease in the esophagus and lymph nodes was significantly more likely with G3 tumors. Median follow-up was 63 months and absolute survival, overall survival, and disease-free survival were all significantly worse in patients with G3 tumors. Further, even with pCR, patients with G3 tumors had significantly worse survival. CONCLUSIONS: This study showed that response to neoadjuvant therapy was not affected by tumor differentiation. However, poor differentiation was associated with worse survival compared with patients with G1/2 tumors, even among those with pCR. These results suggest that poor differentiation should be considered as an added risk factor for clinical staging in patients with locally advanced esophageal adenocarcinoma.

Ventricular tachycardia in the setting of a large cardiac fibroma in a pediatric patient.

Ventricular tachycardia and cardiac tumors are both extremely rare diagnoses in pediatric patients. We report a pediatric case of cardiac fibroma that was noted during the work up of ventricular tachycardia in a young patient concomitantly diagnosed with severe acute respiratory syndrome coronavirus 2.

SARS-CoV-2 exposures among healthcare workers in New York City.

BACKGROUND: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has had a significant impact on hospitals, including the occupational health departments in charge of handling healthcare worker (HCW) staffing during high rates of exposure and infection of HCWs. HCWs who were exposed to a patient or community member infected with SARS-CoV-2 were required to isolate from work for a minimum of 14 days from the date of exposure. AIMS: This study was aimed to assess the relative risk of SARS-CoV-2 infection following different types of workplace and community exposures. METHODS: We analyzed the details of workplace and community exposures of HCWs to SARS-CoV-2 at Montefiore Medical Center in New York between 22 June 2020 and 22 November 2020. RESULTS: Of 562 HCW SARS-CoV-2 exposures analyzed, 218 were from the community and 345 were from the workplace. Twenty-nine per cent of community exposures resulted in infection, which was significantly greater than workplace exposure infection (2%). Household community exposures resulted in a larger frequency of infection than non-household community exposures. Of the seven infections after workplace exposures, five had qualifying exposures to a co-worker and two were exposed to an infected patient during a non-aerosolized procedure. CONCLUSIONS: HCW exposure to SARS-CoV-2 continues to present staffing challenges to healthcare systems. Even with deviations from standard personal protective equipment protocol, workplace exposures resulted in low frequencies of infection. In our study, the primary source of HCW infection was exposure in the community. Our findings support investing in efforts to educate around continued masking and social distancing in the community in addition to interventions targeted at addressing vaccine hesitancy.

Small Bowel Adenocarcinoma Arising in an Iatrogenically Created Jejunosigmoid Bypass.

We believe this to be the first case report of jejunosigmoid bypass harboring small bowel adenocarcinoma. The mechanism of malignant degeneration could be similar to that of carcinogenesis of ureterosigmoidostomy that is of historical interest. This case represents an example of why it is imperative for surgeons to be diligent in their preparation and workup of a patient before a complex operation, especially in patients with peculiar or unknown surgical histories.

Persistent N2 After Induction Is Not a Contraindication to Surgery for Lung Cancer.

BACKGROUND: Surgical management for potentially resectable stage IIIA-N2 non-small cell lung cancer (NSCLC) is controversial. For some, persistent N2 disease after induction therapy is a contraindication to resection. We examined outcomes of a well-selected surgical cohort of postinduction IIIA-N2 NSCLC patients with persistent N2 disease. METHODS: We retrospectively reviewed all resected clinical IIIA-N2 NSCLC patients from 2001 to 2018. Thorough preoperative staging, including invasive mediastinal staging, was performed. Those with nonbulky N2 disease, appropriate restaging, and potential for a margin-negative resection were included. After resection, patients were classified as having persistent N2 disease or mediastinal downstaging (N2 to >N0/N1). Persistent N2 patients were further classified as uncertain resection (R[un]) or complete resection (R0) according to the International Association for the Study of Lung Cancer definition. Kaplan-Meier survival analysis was used. RESULTS: Fifty-four patients met inclusion criteria. After induction, 31 patients (57%) demonstrated persistent N2 disease, and 23 patients (43%) had mediastinal downstaging. Preinduction invasive mediastinal staging was performed in 98.1%. Most had clinical single-station N2 disease (75.9%). Margin-negative resections were performed in 100%. Eight patients were reclassified as R(un) due to positive highest sampled mediastinal station. The median overall survival for persistent N2 was 26 months for R(un) and 69 months for R0. Overall survival for the downstaged group was 67 months (P = .31). CONCLUSIONS: Overall survival for patients with non-R(un) or persistent N2 (true R0) was similar to those with mediastinal downstaging. Well-selected patients with persistent N2 disease experience reasonable survival after resection and should have surgery considered as part of their multimodality treatment. This study underscores the importance of classifying the extent of mediastinal involvement for persistent N2 patients, supporting the proposed International Association for the Study of Lung Cancer R(un) classification.

Implications of Adverse Biological Factors and Management of Solitary Fibrous Tumors of the Pleura.

Solitary fibrous tumors arise in many locations throughout the body and are genetically and histologically considered a single disease. Solitary fibrous tumors of the pleura (SFTP) are the most common tumor of this disease. Most of the SFTPs are treated with surgery alone, and chemotherapy and radiotherapy do not seem to play a role in treatment. Tumor size and unfavorable histology are risk factors for malignant potential. Incomplete resection is an important risk factor for recurrence.

The postoperative use of Impella as a ventricular assist device in high-risk patients undergoing coronary artery bypass surgery: A case series and comparison.

INTRODUCTION: Prophylactic placement of intra-aortic balloon pumps (IABPs) for hemodynamic support has been used in high-risk patients undergoing coronary artery bypass grafting (CABG) surgery. The use of the Impella CP (ICP) heart pump in high-risk patients undergoing CABG has not been reported. In this study, we report our experience using ICP and IABP devices in high-risk patients during the postoperative period. METHODS: This is a case series and retrospective comparison of ICP vs IABP at a single institution using data from 2017. Twenty-eight patients underwent postoperative placement of either the ICP or an IABP. Nineteen patients received IABP and nine received the ICP heart pump. Patient characteristics, comorbidities, and complications were compared using bivariate analysis. Exact logistic regression was used to compare risk-adjusted mortality. RESULTS: There were no statistically significant differences in epidemiologic characteristics, risk factors, or outcomes between both groups, except the ICP group had a lower preoperative left ventricular ejection fraction (22.5 vs 35; P = .028). Exact logistic regression analysis did not show a difference in 30-day mortality between both groups (P = .086). CONCLUSION: The postoperative use of the ICP heart pump, to support high-risk patients undergoing CABG, is a safe option. This practice has allowed us to perform CABG on sicker patients, specifically with depressed ejection fractions, with comparable results to the IABP. Further studies with larger patient populations are needed to draw definitive conclusions, but this pilot study demonstrates a possible expanded use of the Impella device.

Techniques of video-assisted thoracoscopic surgery lobectomy and critical review of published data.

Lung cancer resection techniques have gone through many changes and adaptations. Traditional thoracotomy provided sufficient visualization to fully resect the lobe as well as adequate lymph node dissection. Many thought that this allowed for the most accurate surgical staging of a lung cancer, but subjected the patient to longer hospital stays and increased morbidity and mortality. As with many major surgical operations there has been a culture shift toward minimally invasive techniques, but the adoption has been slow. We present the technique of video-assisted thoracoscopic surgery lobectomy and the literature supporting its use in the treatment of early-stage lung cancer.

Lobectomy for Non-Small Cell Lung Cancer by Video-Assisted Thoracic Surgery: Effects of Cumulative Institutional Experience on Adequacy of Lymphadenectomy.

BACKGROUND: Because video-assisted thoracic surgery (VATS) lobectomies are increasingly being performed by thoracic surgeons, the adequacy of lymph node clearance by VATS compared with thoracotomy has been questioned, raising the possibility that patients are being understaged. One factor that may be overlooked in published studies is the learning curve of the surgeons and surgical volume in the adoption of VATS lobectomy. This study examined the effect of cumulative institutional VATS lobectomy experience on the adequacy of lymphadenectomy. METHODS: We retrospectively reviewed a prospective database to identify 500 consecutive patients who underwent VATS lobectomy for non-small cell lung cancer (NSCLC) at our institution between 2002 and 2012. For comparative purposes, the cohort was divided into halves, with an early group (first 250 cases) vs a late group (next 250 cases). Clinical and pathologic factors were analyzed. A propensity-matching analysis controlling for age, gender, pathologic stage, and percentage of forced expiratory volume in 1 second was done to compare survival and adequacy of lymphadenectomy. RESULTS: Patients operated on in the late group were significantly older (72 vs 69 years, p = 0.001) and had worse pulmonary functions (median forced expiratory volume in 1 second 83% vs 91%, p < 0.001; median diffusion capacity of the lung for carbon monoxide, 76% vs 85%, p < 0.001). Clinical and pathologic tumor sizes were significantly larger in the late group compared with the early group, with a median of 2.0 vs 1.8 cm (p = 0.002) for clinical T size and median of 2.1 vs 2.0 cm (p = 0.003) for pathologic T size. Patients in the late group had significantly more advanced clinical and pathologic stage distribution. The total number of lymph nodes and the number of nodal stations removed were significantly greater in the late group (p = 0.012) than in the early group (p < 0.001), and same results were obtained after propensity matching. No difference was seen in disease-free survival between the propensity-matched early vs late groups at 3 years (82% vs 85%, p = 0.187). CONCLUSIONS: For patients with NSCLC resected by VATS lobectomy, cumulative institutional experience significantly and positively affects the adequacy of lymphadenectomy. This may be related to the initial surgeon's learning curve with VATS lobectomy. As the experience with VATS lobectomy becomes more mature, the procedure is increasingly being performed on older patients, often with more compromised pulmonary function and more advanced stage disease. Despite the expanded inclusion of older and sicker patients for VATS lobectomy, no compromise was seen in their disease-free survival.

Predictors of Disease-free Survival and Recurrence in Patients with Resected Bronchial Carcinoid Tumors.

BACKGROUND: Bronchial carcinoids are characterized by neuroendocrine differentiation and have distinct biological behavior, recurrence patterns, and prognosis compared with adenocarcinomas or squamous cell carcinomas. Because of their often indolent nature, it has been suggested that routine postoperative imaging surveillance may not be warranted in the majority of patients. This study aims to define the factors that predict disease-free survival (DFS) and recurrence after resection of these tumors, with the goal of identifying high-risk patients for whom image surveillance may be warranted. METHODS: We conducted a retrospective review of a prospective database to identify patients with completely resected bronchial carcinoid tumors. Surgical procedure, histology, pathological stage, follow-up, tumor recurrence, and survival were assessed. RESULTS: One hundred and forty-two patients were identified. Median age was 62 years and the majority was women (106). Surgical procedures included 20 wedge resections, 10 segmentectomies, 99 lobectomies, 3 bilobectomies, 2 pneumonectomies, 6 sleeve resections, and 2 bronchectomies. Pathologic stages included I (81%), II (10%), III (8%), and IV (1%). With a median follow-up of 31 months, there were seven recurrences. The 5- and 10-year overall survival rates were 92% and 75% and DFS rates were 88% and 72%, respectively. There were 34 patients with atypical carcinoids, and 6 (18%) developed recurrence, compared with 1 recurrence (1%) in the group of 108 patients with typical carcinoids (p = 0.0008). For atypical carcinoid tumors, the 5- and 10-year DFS rates were 72% and 32% versus 92% and 85% in typical carcinoid tumors (p = 0.001). Patients with more advanced tumor stage pT2-4 and pathologic N1/N2 nodal metastases had a significantly decreased 5- and 10-year DFS compared with those with early pT1 stage (p = 0.029) or those without nodal disease (p = 0.043). Multivariate Cox regression analyses showed advancing age (p = 0.001), atypical histology (p = 0.021), and advanced tumor stage (p = 0.047) were significant negative predictors for DFS. CONCLUSION: Long-term survival after resection of bronchial carcinoids is common, especially for patients with typical carcinoid tumors. DFS can be negatively influenced by atypical histology, advanced tumor, and nodal statuses. Efforts at postoperative image surveillance should target those patients with such high-risk factors.

Outcomes of lobectomy in patients with severely compromised lung function (predicted postoperative diffusing capacity of the lung for carbon monoxide % ≤ 40%).

RATIONALE: Patients defined as high operative risk by pulmonary function tests are often denied lobectomy or offered potentially less curative options, including sublobar resection or stereotactic body radiation therapy. OBJECTIVES: The aim of this study was to determine the outcomes of lobectomy in a group of patients deemed high risk based on predicted postoperative diffusing capacity of carbon monoxide (DlCO) less than or equal to 40%. METHODS: This is a retrospective review of a prospectively collected database of patients who underwent lobectomy with a predicted postoperative DlCO% less than or equal to 40%. Survival was calculated using the Kaplan-Meier method, and multivariate predictors were determined using regression analysis. MEASUREMENTS AND MAIN RESULTS: Lobectomy was performed in 50 patients with a predicted DlCO less than or equal to 40% (median predicted postoperative DlCO%, 35%). The median age was 71 years, 68% (n = 34) were women, and 84% (n = 42) had an Eastern Cooperative Oncology Group performance status of 0. Eight patients had both predicted postoperative FEV1% or predicted postoperative DlCO% less than or equal to 40%. Thoracoscopic lobectomy was performed in 36% (n = 18) and reoperations in 6% (n = 3). There was no operative mortality. Seventy percent (n = 35) of patients had no complications, with a median length of stay of 5 days. The most frequent complications were pulmonary (14% [n = 7]) and cardiovascular (12% [n = 6]). Four patients (8%) were discharged on home oxygen, and four (8%) required rehabilitation post discharge. Multivariable analyses evaluating the effects of age, sex, comorbidities, smoking status, and operative approach on all-cause morbidity, postoperative home oxygen use, and a composite of the two were performed. Diabetes was found to be a predictor of the composite of all-cause morbidity and postoperative home oxygen use. Overall 5-year survival for the entire cohort was 69% (95% confidence interval, 52-87%). CONCLUSIONS: Lobectomy can be safely performed in select patients considered to be high risk for resection by pulmonary function tests. Additional criteria are needed to assess risk.

Long-term survival after lobectomy for non-small cell lung cancer by video-assisted thoracic surgery versus thoracotomy.

BACKGROUND: Video-assisted thoracic surgery (VATS) lobectomy for non-small cell lung cancer (NSCLC) is increasingly popular. However, the oncologic soundness of VATS for patients with NSCLC as measured by long-term survival has not been proven. The objective here is to determine the overall survival (OS) and disease-free survival (DFS) in two well-matched groups of patients with NSCLC resected by VATS or thoracotomy. METHODS: We conducted a retrospective review of a prospective database to identify patients who had a lobectomy for NSCLC. A propensity score-matched analysis was done with variables of age, sex, smoking history, Charlson comorbidity index, forced expiratory volume in 1 second, lung diffusing capacity for carbon monoxide, histology, and clinical T and N status. Medical records were reviewed and survival was analyzed. RESULTS: After matching, there were 208 patients in each group. Patient and tumor characteristics were similar. The VATS group had a shorter length of stay. More nodes (14.3 versus 11.3; p=0.001) and more nodal stations (3.8 versus 3.1; p<0.001) were removed by thoracotomy. No differences were seen in OS and DFS. Median follow-up was 36 months. More than 90% of patients had clinical stage I disease, with 3- and 5-year OS of 87.4% and 76.5%, respectively, for VATS, and 81.6% and 77.5%, respectively, for thoracotomy (p=0.672). Both the incidence and distribution of recurrence were similar. Multivariate Cox regression analyses of OS and DFS confirmed the noninferiority of VATS. CONCLUSIONS: For patients with clinical stage I NSCLC, VATS lobectomy offered similar OS and DFS compared with thoracotomy. Thoracotomy offers a more thorough lymph node evaluation, and may be appropriate for patients with more advanced clinical disease.

Differences between the pre-menopausal and post-menopausal uterine fibroid vasculature.

OBJECTIVES: To quantitatively examine differences in microvascular density between fibroid and myometrial tissue from fibroid uteri removed at hysterectomy, both before and after the menopause, and with hormone replacement therapy. METHODS: Factor VIII immunostaining of formalin fixed tissues was used to identify blood vessels, and the vessels counted by an investigator blinded to tissue type or menopausal status. RESULTS: The mean myometrial: fibroid MVD ratio was 2.38 higher in the post-menopausal group (95% CI: 0.12, 4.65, p=0.0474) than in the pre-menopausal group, with the hormone therapy (HT)-using post-menopausal group lying in between. An increase in microvascular density in the myometrium after the menopause was responsible for most of the change in ratios seen between the pre and post-menopausal pairs. There was a trend to increasing myometrial MVD with increasing number of years post-menopause. CONCLUSIONS: Myometrial microvascular density increases markedly after the menopause, while fibroid microvascular density does not alter. Thus, the difference between myometrial and fibroid vasculature becomes greater after the menopause. The implications of this for the treatment of fibroids in post-menopausal women is discussed.

Myometrial microvascular endothelial cells express oxytocin receptor.

OBJECTIVE: 1. To establish whether microvascular endothelial cells from the human myometrium (MMECs) express oxytocin receptor, and to compare its expression levels relative to HUVECs. 2. To verify an up-regulation of oxytocin receptor expression in MMECs as a result of vascular endothelial growth factor (VEGF), which had been found in a previous study. DESIGN: Laboratory scientific study. SETTING: University department. POPULATION OR SAMPLE: Myometrial biopsies from 12 hysterectomy specimens. METHODS: MMECs and HUVECs were established in vitro. Immunohistochemistry of in vitro cultures was performed to investigate protein expression of the oxytocin receptor. Semi-quantitative RT-PCR and Northern blots were performed to examine the presence and relative abundance of oxytocin receptor mRNA in MMECs and HUVECs, and in both cell types with and without VEGF. Total RNA from oxytocin acetate (100 nmol/L) and vehicle stimulated endothelial cell cultures was used to examine gene expression differences on a 10.5K cDNA microarray. MAIN OUTCOME MEASURES: Oxytocin receptor mRNA and protein; gene expression anlysis. RESULTS: Oxytocin receptor mRNA and protein was present in MMECs. The level of expression was the same as for the HUVECs, but much less than the pregnant myometrium. No effect on gene expression could be demonstrated by gene expression microarray following 10 hours of oxytocin stimulation. Twenty-four hours of VEGF stimulation did not significantly alter oxytocin receptor mRNA expression in MMECs or HUVECs. CONCLUSION: The myometrial microvasculature expresses oxytocin receptor. This finding means that oxytocin may exert some of its effects on the myometrial microvasculature. No evidence could be found for a transcriptional effect of oxytocin stimulation in this study, but further work on the role of the myometrial vessel oxytocin receptor is needed.

Microarray analysis of VEGF-responsive genes in myometrial endothelial cells.

There is evidence that the vasculature of different organs display different functional characteristics in response to cytokines and growth factors. The aim of this study was to use cDNA gene expression microarray to analyse changes in gene expression following stimulation of myometrial microvascular endothelial cells (MMECs) with vascular endothelial growth factor (VEGF). Primary isolates of MMECs were obtained from fresh hysterectomy specimens and purified with magnetic beads. Cells were stimulated with 15 ng/ml VEGF for 3, 6 and 12 h, and two unstimulated experiments served as controls. A total of six arrays was performed over these time-points. A total of 110 genes were identified as up-regulated by VEGF, 19% of which (21 genes) have previously been reported as up-regulated by VEGF or by angiogenesis. Among the novel genes to be up-regulated by VEGF were brain-derived growth factor, oxytocin receptor and estrogen sulphotransferase. The significance of the genes identified in the physiological and pathological functioning of the myometrial vasculature is discussed.

The use of computational methods in the discovery and design of kinase inhibitors.

The recent success of the first FDA-approved small-molecule tyrosine kinase inhibitor Gleevec (STI-571, imatinib mesylate) in the treatment of chronic myelogenous leukemia (CML) has focused attention on the potential therapeutic usefulness of inhibitors of other kinase targets. This review shall highlight recent applications of computational chemistry methods, comprising both ligand-based and structure-based approaches, in the discovery and design of kinase inhibitors. In particular, we will focus on ATP-competitive inhibitors of selected kinase targets of therapeutic importance.