Risk Factors Associated With Acute Kidney Injury in Traumatic Brain Injury Patients Treated With Hypertonic Saline: A Retrospective Study.

Background: Hypertonic saline (HTS) is essential pharmacologic treatment for traumatic brain injury (TBI). Previous studies associate HTS with acute kidney injury (AKI), however evidence in TBIs is limited. Objective: This study examines factors associated with AKI in patients requiring HTS for TBI. Methods: This retrospective study was performed at a Level-1 Trauma, Academic Medical Center. Inclusion criteria were TBI, age ≥12 years, ICU length of stay ≥72 hours, and administration of ≥24 hours of continuous HTS or 500 mL of HTS boluses. The primary outcome was identifying factors associated with AKI. Secondary outcomes included correlation between chloride load and level with development of AKI. Chloride load was calculated from HTS and non-HTS sources. Results: Of 129 patients included, 18 (14%) developed AKI. Maximum sodium level was higher in the AKI group (P < 0.0001). Hyperchloremia (Cl ≥ 115 mEq/L) was more common in the AKI group (100% vs 81%, P = 0.0428). Maximum and change in serum chloride were higher in the AKI group (median 128 vs 123 mEq/L, P = 0.0026 and +24 mEq/L vs +17 mEq/L, P = 0.0084, respectively). Logistic regression analysis indicated an OR 1.095 times higher [95% CI (1.022, 1.172)] for developing AKI for every one mEq/L increase in maximum chloride level and an OR 1.032 [95% CI (1.006, 1.058)] for developing AKI for every 1-year increase in age. There was no difference in total chloride load between groups (P = 0.2143). Non-HTS sources provided more than 40% of total chloride load in both groups. Conclusion: Chloride level, and age may be associated with AKI in TBI patients treated with HTS.

Treatment Adherence Rates and Long-Term Mortality in a Quaternary Multidisciplinary Heart Team: An Observational Cohort.

BACKGROUND: A multidisciplinary heart team (HT) approach to patients with complex coronary artery disease has a class IB recommendation, yet there are limited data on adherence to HT treatment recommendations and long-term clinical follow-up. The objective of this study was to assess adherence rates to HT recommendations and assess long-term mortality rates among patients with complex CAD. METHODS AND RESULTS: Six hundred eighty-four sequential HT cases for complex coronary artery disease from January 2015 to May 2017 were reviewed. After excluding cases with significant comorbid valve disease, baseline characteristics were compared based on HT treatment recommendations: optimal medical therapy, percutaneous coronary intervention, and coronary artery bypass grafting. Adherence rates were manually extracted, and 5-year mortality rates were obtained from the Michigan Death Registry. Seventy-two percent of 405 included patients were men (mean age 66±11 years), with high rates of medical comorbidities. Estimated surgical risk scores were lowest in the coronary artery bypass grafting group. Optimal medical therapy was recommended in 138 patients (34%), percutaneous coronary intervention in 95 (23%), and coronary artery bypass grafting in 172 (42%). Adherence to HT recommendations across groups was high (96%) and did not differ between treatment groups. Over 5 years of follow-up, there were 119 deaths, resulting in a cumulative mortality rate of 29%. CONCLUSIONS: In the largest HT cohort in the United States to date, high rates of adherence to HT recommendations were observed among high-risk patients with coronary artery disease. High rates of adherence to HT recommendations were observed irrespective of treatment group recommendation, suggesting that HT recommendations were individualized and acceptable to both patients and physicians alike.

Protocol for in vitro co-culture, proliferation, and cell cycle analyses of patient-derived leukemia cells.

Leukemia niche impacts quiescence; however, culturing patient-derived samples ex vivo is technically challenging. Here, we present a protocol for in vitro co-culture of patient-derived xenograft acute lymphoblastic leukemia (PDX-ALL) cells with human mesenchymal stem cells (MSCs). We describe steps for labeling PDX-ALL cells with CellTrace Violet dye to demonstrate MSC-primed PDX-ALL cycling. We then detail procedures to identify MSC-primed G0/quiescent PDX-ALL cells via Hoechst-33342/Pyronin Y live cell cycle analysis. For complete details on the use and execution of this protocol, please refer to Pal et al.1,2.

Nucleolar Localization of the RNA Helicase DDX21 Predicts Survival Outcomes in Gynecologic Cancers.

Cancer cells with DNA repair defects (e.g., BRCA1/2 mutant cells) are vulnerable to PARP inhibitors (PARPi) due to induction of synthetic lethality. However, recent clinical evidence has shown that PARPi can prevent the growth of some cancers irrespective of their BRCA1/2 status, suggesting alternative mechanisms of action. We previously discovered one such mechanism in breast cancer involving DDX21, an RNA helicase that localizes to the nucleoli of cells and is a target of PARP1. We have now extended this observation in endometrial and ovarian cancers and provided links to patient outcomes. When PARP1-mediated ADPRylation of DDX21 is inhibited by niraparib, DDX21 is mislocalized to the nucleoplasm resulting in decreased rDNA transcription, which leads to a reduction in ribosome biogenesis, protein translation, and ultimately endometrial and ovarian cancer cell growth. High PARP1 expression was associated with high nucleolar localization of DDX21 in both cancers. High nucleolar DDX21 negatively correlated with calculated IC50s for niraparib. By studying endometrial cancer patient samples, we were able to show that high DDX21 nucleolar localization was significantly associated with decreased survival. Our study suggests that the use of PARPi as a cancer therapeutic can be expanded to further types of cancers and that DDX21 localization can potentially be used as a prognostic factor and as a biomarker for response to PARPi. SIGNIFICANCE: Currently, there are no reliable biomarkers for response to PARPi outside of homologous recombination deficiency. Herein we present a unique potential biomarker, with clear functional understanding of the molecular mechanism by which DDX21 nucleolar localization can predict response to PARPi.

Contemporary outcomes of surgical aortic valve replacement in patients referred for a transcatheter approach.

OBJECTIVES: The purpose of this study is to examine which patients referred to our structural valve clinic for potential transcatheter aortic valve replacement (TAVR) are receiving surgical aortic valve replacement (SAVR) whether due to unsuitable anatomy for TAVR versus other reasons. METHODS: Individuals referred for TAVR from January 2019 to March 2022, who ultimately underwent SAVR were examined, retrospectively. Patients were divided into 2 surgical groups: TAVR was technically unsuitable (SAVR-TU) and those in which TAVR was technically feasible (SAVR-TF). RESULTS: 215 patients referred for TAVR underwent SAVR with 61 (28.4%) patients in the SAVR-TU group and 154 (71.6%) in the SAVR-TF group. The SAVR-TU group were more commonly female (52.5% vs 23.4%, p < 0.0001), had a higher incidence of stroke at baseline (9.8% vs 2.0%, p = 0.017) were frailer (5-m gait 5.2 s vs 4.7 s, p = 0.0035), and had a higher Society of Thoracic Surgery risk score (2.2 vs 1.7, p = 0.04). In the SAVR-TU group, unsuitability for TAVR was due to inadequate aortic root anatomy (86.9%), and poor peripheral access (6.6%). In the SAVR-TF group, the most common reasons for SAVR referral were concomitant coronary artery disease (42.9%), bicuspid aortic valve disease (16.9%), and concomitant aortic aneurysm (10.4%). Overall, in-hospital mortality was 1.4% with no difference between both groups. One-year survival was 96.7%. CONCLUSION: Despite a higher trend of aortic stenosis being treated with TAVR, higher risk patients unsuitable for TAVR can have SAVR with excellent outcomes. Moreover, patients with AS and concomitant other pathology should be evaluated for cardiac surgery.

Neoadjuvant Chemotherapy and Radiation Improves Recurrence-free and Overall Survival in Resectable and Borderline Resectable Pancreatic Ductal Adenocarcinoma.

OBJECTIVE: The objective of this study is to analyze the outcomes of patients with resectable/borderline resectable PDAC who receive total neoadjuvant therapy vs upfront surgery. METHODS AND ANALYSIS: Patients who were treated at a single institution from 2006 to 2021 were included. The primary outcome was overall survival (OS). Secondary outcomes included disease free survival (DFS), rates of lymph node positivity, and R0 resection. All survival analyses were performed with intention-to-treat. RESULTS: 26 patients received neoadjuvant chemotherapy and radiation (TNT), 28 received neoadjuvant chemotherapy only (NAC), and 168 received upfront surgery. Demographics were comparable across all three groups. Patients who received TNT or NAC had longer OS and DFS compared to the surgery first patients (P < .01). Patients who received TNT had a lymph node positivity rate of 0% at time of surgery compared to 5.3% and 13.3% in the NAC and surgery-first groups, respectively (P < .01). The rate of R0 resection did not differ between groups (P = .17). CONCLUSION: Patients with resectable/borderline resectable PDAC who receive neoadjuvant therapy have longer OS and RFS relative to those who receive upfront surgery.

Comparison of Low Dose Recombinant Factor VIIa and 4-Factor Prothrombin Complex Concentrate for Treatment of Bleeding Related to Cardiac Surgery.

Background: Recombinant factor VIIa (rFVIIa) and prothrombin concentrate complex (PCC) are used for uncontrolled bleeding in cardiac surgery (CS), however, there are limited direct comparisons of these agents. Objective: To evaluate the efficacy and safety of rFVIIa and PCC in CS related bleeding. Methods: This retrospective study included adult CS patients who received either low dose rFVIIa (<30 mcg/kg) or 4-factor PCC. The primary outcome was transfusion requirements of packed red blood cells (pRBC) within 6 hours of factor administration. Secondary efficacy outcomes included transfusion requirements 0-18 hours, doses of additional factor product, thrombotic events, and acute kidney injury (AKI). Results: A total of 179 patients were included (n = 78 rFVIIa; n = 101 PCC). Of patients who received blood products, there was no difference in the requirement of pRBCs within 6 hours (73.8 vs 68.9%, P = .5359) or in the median amount of pRBC transfused (500 mL vs 640 mL, P = .0723) in the rFVIIa and PCC groups respectively. Patients in the PCC group were more likely to require additional factor products (24.4% vs 47.5%, P = .0015), develop AKI (12.8% vs 25.7%, P = .0325), have longer ICU lengths of stay [2 (IQR 1-5) vs 4 (IQR 2-6), P = .0487] and greater in-hospital mortality (2.6% vs 10.9%, P = .033). There was no difference in thrombotic events. Conclusion: Although, there was no difference in pRBC transfusion requirements between PCC and rFVIIa, more patients in the PCC group required additional factor products and had increased adverse effects. Further comparisons of PCC and rFVIIa are warranted.

Low-Dose Rivaroxaban as Extended Prophylaxis Reduces Postdischarge Venous Thromboembolism in Patients With Malignancy and IBD.

BACKGROUND: Despite guidelines suggesting the use of extended prophylaxis for prevention of venous thromboembolism in patients with colorectal cancer and perhaps IBD, routine use is low and scant data exist regarding oral forms of therapy. OBJECTIVE: The purpose was to compare the incidence of postdischarge venous thromboembolism in patients given extended prophylaxis with low-dose rivaroxaban. DESIGN: We used propensity matching to compare pre- and postintervention analyses from a 2-year period before instituting extended prophylaxis. SETTING: All colorectal patients at a single institution were prospectively considered for extended prophylaxis. PATIENTS: Patients with a diagnosis of IBD or colorectal cancer who underwent operative resection were included. INTERVENTIONS: Those considered for extended prophylaxis were prescribed 10 mg of rivaroxaban for 30 days postsurgery. MAIN OUTCOME MEASURES: The primary outcome was venous thromboembolism incidence 30 days postdischarge. The secondary outcome was bleeding rates, major or minor. RESULTS: Of the 498 patients considered for extended prophylaxis, 363 were discharged with rivaroxaban, 81 on baseline anticoagulation, and 54 without anticoagulation. Propensity-matched cohorts based on stoma creation, operative approach, procedure type, and BMI were made to 174 historical controls. After excluding cases of inpatient venous thromboembolism, postoperative rates were lower in the prospective cohort (4.8% vs 0.6%, p = 0.019). In the prospective group, 36 episodes of bleeding occurred, 26 (7.2%) were discharged with rivaroxaban, 8 (9.9%) discharged on other anticoagulants, and 2 (3.7%) with no postoperative anticoagulation. Cases of major bleeding were 1.1% (4/363) in the rivaroxaban group, and each required intervention. LIMITATIONS: The study was limited to a single institution and did not include a placebo arm. CONCLUSIONS: Among patients with IBD and colorectal cancer, extended prophylaxis with low-dose rivaroxaban led to a significant decrease in postdischarge thromboembolic events with a low bleeding risk profile. See Video Abstract . RIVAROXABN EN DOSIS BAJAS COMO PROFILAXIS PROLONGADA REDUCE LA TROMBOEMBOLIA VENOSA POSTERIOR AL ALTA, EN PACIENTES CON NEOPLASIAS MALIGNAS Y ENFERMEDAD INFLAMATORIA INTESTINAL: ANTECEDENTES:A pesar de las normas que sugieren el uso de profilaxis extendida para la prevención del tromboembolismo venoso en pacientes con cáncer colorrectal y tal vez enfermedad inflamatoria intestinal, el uso rutinario es bajo y existen escasos datos sobre las formas orales de terapia.OBJETIVO:Comparar la incidencia de tromboembolismo venoso posterior al alta, en pacientes que recibieron profilaxis prolongada con dosis bajas de rivaroxabán.DISEÑO:Utilizamos el emparejamiento de propensión para comparar un análisis previo y posterior a la intervención de un período de 2 años antes de instituir la profilaxis extendida.AJUSTE:Todos los pacientes colorrectales en una sola institución fueron considerados prospectivamente para profilaxis extendida.PACIENTES:Incluidos pacientes con diagnóstico de enfermedad inflamatoria intestinal o cáncer colorrectal sometidos a resección quirúrgica.INTERVENCIONES:A los considerados para profilaxis extendida se les prescribió 10 mg de rivaroxabán durante 30 días postoperatorios.PRINCIPALES MEDIDAS DE RESULTADO:El resultado primario fue la incidencia de tromboembolismo venoso 30 días después del alta. El resultado secundario fueron las tasas de hemorragia, mayor o menor.RESULTADOS:De los 498 pacientes considerados para profilaxis extendida, 363 fueron dados de alta con rivaroxabán, 81 con anticoagulación inicial y 54 sin anticoagulación. Se realizaron cohortes emparejadas por propensión basadas en la creación de la estoma, abordaje quirúrgico, tipo de procedimiento y el índice de masa corporal en 174 controles históricos. Después de excluir los casos de tromboembolismo venoso hospitalizado, las tasas posoperatorias fueron más bajas en la cohorte prospectiva (4,8% frente a 0,6%, p = 0,019). En el grupo prospectivo ocurrieron 36 episodios de hemorragia, 26 (7,2%) fueron dados de alta con rivaroxaban, 8 (9,9%) fueron dados de alta con otros anticoagulantes y 2 (3,7%) sin anticoagulación posoperatoria. Los casos de hemorragia mayor fueron del 1,1% (4/363) en el grupo de rivaroxabán y cada uno requirió intervención.LIMITACIONES:Limitado a una sola institución y no incluyó un grupo de placebo.CONCLUSIONES:Entre los pacientes con enfermedad inflamatoria intestinal y cáncer colorrectal, la profilaxis extendida con dosis bajas de rivaroxabán condujo a una disminución significativa de los eventos tromboembólicos posteriores al alta, con un perfil de riesgo de hemorragia bajo. (Traducción-Dr. Fidel Ruiz Healy).

Vulvar cancer management and wrangling recurrent disease: A report from the society of gynecologic oncology journal club.

The Society of Gynecologic Oncology (SGO) Journal Club webinar series is an open forum that invites national experts to discuss the literature pertaining to important topics in the management of gynecologic cancers. On August 14th, 2023, SGO hosted a journal club focused on the management of upfront and recurrent vulvar cancer. Our discussants included Dr. Brian M Slomovitz from Mount Sinai Medical Center in Miami Beach, Dr. Emi Yoshida from the University of California San Francisco Helen Diller Family Comprehensive Cancer Center, and Dr. Lilian Gien from the University of Toronto Sunnybrook Odette Cancer Center. During the discussion,we reviewed the progression of vulvar cancer surgery from en bloc resection of the vulva and groins, to partial radical vulvectomy and sentinel lymph nodes. We also reviewed the management of node positive vulvar cancer including published and accruing Groningen International Study on Sentinel Nodes in Vulvar Cancer (GROINSS) trials and other sentinel trials from the Gynecologic Oncology Group (GOG). Here we will also review the literature on the management of recurrent vulvar cancer, highlighting current treatment options and ongoing clinical trials. The following is a report of the journal club presentation.

Does Hispanic ethnicity play a role in outcomes for diverticular surgery in the USA?

OBJECTIVE: The aim of this study is to investigate whether origins of ethnicity affect the outcomes of surgery for diverticulitis in the USA. DESIGN: The American College of Surgeons National Surgical Quality Improvement Programme database from 2008 to 2017 was used to identify patients undergoing colectomy for diverticulitis. Patient demographics, comorbidities, procedural details and outcomes were captured and compared by ethnicity status. RESULTS: A total of 375 311 surgeries for diverticulitis were included in the final analysis. The average age of patients undergoing surgery for diverticulitis remained consistent over the time frame of the study (62 years), although the percentage of younger patients (age 18-39 years) rose slightly from 7.8% in 2008 to 8.6% in 2017. The percentage of surgical patients with Hispanic ethnicity increased from 3.7% in 2008 to 6.6% of patients in 2017. Hispanic patients were younger than their non-Hispanic counterparts (57 years vs 62 years, p<0.01) at time of surgery. There were statistically significant differences in the proportion of laparoscopic cases (51% vs 49%, p<0.01), elective cases (62% vs 66%, p<0.01) and the unadjusted rate of postoperative mortality (2.8% vs 3.4%, p<0.01) between Hispanic patients compared with non-Hispanic patients, respectively. Multivariable logistic regression models did not identify Hispanic ethnicity as a significant predictor for increased morbidity (p=0.13) or mortality (p=0.80). CONCLUSION: Despite a significant younger population undergoing surgery for diverticulitis, Hispanic ethnicity was not associated with increased rates of emergent surgery, open surgery or postoperative complications compared with a similar non-Hispanic population.

Incidence and clinical relevance of paraneoplastic syndromes in patients with renal cell carcinoma.

BACKGROUND: Paraneoplastic syndromes (PNS) are defined as the signs and symptoms attributed to cytokines or hormones released from a tumor or a patient's immune system. PNS have been reported with many cancers for decades and data supporting their relevance in renal cell carcinoma (RCC) are largely historical. The widespread use of electronic medical record (EMR) systems provides a more robust method to capture data. The objective of this study was to establish contemporary data regarding the incidence and relevance of PNS in patients undergoing nephrectomy for suspected RCC. METHODS: In this retrospective single-institution study, 851 patients undergoing nephrectomy for suspected RCC between 2011 and 2018 were assessed for the presence or absence of PNS as defined by laboratory abnormalities. Factors associated with PNS and with all-cause mortality were examined. RESULTS: The incidence of PNS was 33.1% among 851 patients prior to nephrectomy. The most prevalent PNS were anemia (22.4%), thrombocytosis (7.5%), and elevated C-reactive protein (CRP) (7.4%). PNS were more common in women (39.2% vs. 29.4%, p = 0.0032) and higher stage RCC (31.1% of stage I vs. 54.2% of stage IV, p = 0.0036). Factors associated with the presence of PNS in multivariable analysis included female gender, high comorbidity, and stage IV RCC. Prenephrectomy PNS were associated with poorer survival in multivariable analysis (HR: 2.12, p = 0.0002). Resolution of PNS occurred in 52.1% of patients after nephrectomy, including 55.2% with stage I to III and 38.5% with stage IV RCC (p = 0.10). CONCLUSIONS: Using EMR data, laboratory evidence of PNS was present in one-third of a contemporary cohort of patients undergoing nephrectomy, with >50% of PNS resolving after surgery. Consistent with prior reports, PNS are more common in higher-stage RCC and are associated with poorer survival in RCC patients.

Correction of Breast Ptosis in Immediate Breast Reconstruction.

Nipple-sparing mastectomy is psychologically advantageous and can result in superior cosmetic outcomes. However, nipple position adjustment is challenging, and ischemic complications may arise. For patients who require timely mastectomies and reconstructions, concurrent mastopexy may prevent nipple malposition and reduce the risk for future corrections. Methods: A retrospective chart review of all patients undergoing immediate prosthetic reconstruction after nipple-sparing mastectomy were analyzed. Data regarding patient characteristics; surgical indications; reconstructive modality, including presence or absence of simultaneous nipple lift; and early and late complications were examined. Results: In total, 142 patients underwent 228 nipple-sparing mastectomies and prosthetic reconstructions. Correction of ptosis (lift) was performed in 22 patients and 34 breasts. The remaining 122 patients and 194 breasts did not receive mastopexy (no-lift). Two patients received bilateral reconstructions involving both lift and no-lift. Comparing the lift and no-lift cohorts demonstrated no differences in major complications (47.1% versus 57.7%; P = 0.25) and minor complications (76.5% versus 74.7%; P = 0.83). Control for plane of implant placement also did not show differences in major (P = 0.31) or minor (P = 0.97) complications. Similarly, control of application of acellular dermal matrix found major (P = 0.25) and minor (P = 0.83) complications uniform and not affected by lift status. Nipple lift distance was not associated with increased major (P = 0.10) complications. Conclusion: Simultaneous correction of nipple position in immediate prosthetic breast reconstruction seem safe with uniform complications rates that are unaffected by acellular dermal matrix use or plane of implant placement.

Targeting N-cadherin (CDH2) and the malignant bone marrow microenvironment in acute leukaemia.

This review discusses current research on acute paediatric leukaemia, the leukaemic bone marrow (BM) microenvironment and recently discovered therapeutic opportunities to target leukaemia-niche interactions. The tumour microenvironment plays an integral role in conferring treatment resistance to leukaemia cells, this poses as a key clinical challenge that hinders management of this disease. Here we focus on the role of the cell adhesion molecule N-cadherin (CDH2) within the malignant BM microenvironment and associated signalling pathways that may bear promise as therapeutic targets. Additionally, we discuss microenvironment-driven treatment resistance and relapse, and elaborate the role of CDH2-mediated cancer cell protection from chemotherapy. Finally, we review emerging therapeutic approaches that directly target CDH2-mediated adhesive interactions between the BM cells and leukaemia cells.

Next generation organoid engineering to replace animals in cancer drug testing.

Cancer therapies have several clinical challenges associated with them, namely treatment toxicity, treatment resistance and relapse. Due to factors ranging from patient profiles to the tumour microenvironment (TME), there are several hurdles to overcome in developing effective treatments that have low toxicity that can mitigate emergence of resistance and occurrence of relapse. De novo cancer development has the highest drug attrition rates with only 1 in 10,000 preclinical candidates reaching the market. To alleviate this high attrition rate, more mimetic and sustainable preclinical models that can capture the disease biology as in the patient, are required. Organoids and next generation 3D tissue engineering is an emerging area that aims to address this problem. Advancement of three-dimensional (3D) in vitro cultures into complex organoid models incorporating multiple cell types alongside acellular aspects of tissue microenvironments can provide a system for therapeutic testing. Development of microfluidic technologies have furthermore increased the biomimetic nature of these models. Additionally, 3D bio-printing facilitates generation of tractable ex vivo models in a controlled, scalable and reproducible manner. In this review we highlight some of the traditional preclinical models used in cancer drug testing and debate how next generation organoids are being used to replace not only animal models, but also some of the more elementary in vitro approaches, such as cell lines. Examples of applications of the various models will be appraised alongside the future challenges that still need to be overcome.

Preoperative Immuno-Nutrition and Complications After Colorectal Surgery: Results of a 2-Year Prospective Study.

INTRODUCTION: Preoperative immuno-nutrition has been associated with reductions in infectious complications and length of stay, but remains unstudied in the setting of an enhanced recovery protocol. The objective was to evaluate outcomes after elective colorectal surgery with the addition of a preoperative immuno-nutrition supplement. METHODS: In October 2017, all major colorectal surgeries were given an arginine-based supplement prior to surgery. The control group consisted of cases within the same enhanced recovery protocol from three years prior. The primary outcome was a composite of overall morbidity. Secondary outcomes were infectious complications and length of stay with subgroup analysis based on degrees of malnutrition. RESULTS: Of 826 patients, 514 were given immuno-nutrition prospectively and no differences in complication rates (21.5% versus 23.9%, P = 0.416) or surgical site infections (SSIs) (6.4% versus 6.9%, P = 0.801) were observed. Hospitalization was slightly shorter in the immuno-nutrition cohort (5.0 [3.0, 7.0], versus 5.5 days [3.6, 7.9], P = 0.002). There was a clinically insignificant difference in prognostic nutrition index scores between cohorts (35.2 ± 5.6 versus 36.1 ± 5.0, P = 0.021); however, subgroup analysis (< 33, 34-38 and > 38) failed to demonstrate an association with complications (P = 0.275) or SSIs (P = 0.640) and immuno-nutrition use. CONCLUSIONS: Complication rates and SSIs were unchanged with the addition of immuno-nutrition before elective colorectal surgery. The association with length of stay is small and without clinical significance; therefore, the routine use of immuno-nutrition in this setting is of questionable benefit.

Randomized Feasibility Trial of Prophylactic Radiofrequency Ablation to Prevent Atrial Fibrillation after Cardiac Surgery.

OBJECTIVE: Evaluate the feasibility of prophylactic radiofrequency isolation of the pulmonary veins, with left atrial appendage amputation, to reduce the incidence of postoperative atrial fibrillation (POAF) after cardiac surgery in patients aged 70 and older. METHODS: The Federal Food and Drug Administration granted an investigational device exemption to utilize a bipolar radiofrequency clamp for prophylactic pulmonary vein isolation in a limited, feasibility trial. Sixty-two patients without prior dysrhythmias, were prospectively randomized to undergo either their index cardiac surgical procedure, or bilateral pulmonary vein isolation and left atrial appendage amputation during their cardiac operation. The primary outcome was occurrence of in-hospital POAF. Subjects were on 24-hour telemetry until discharge. Dysrhythmias, any episode of atrial fibrillation > 30 seconds, were confirmed by electrophysiologists blinded to the study. RESULTS: Sixty patients, mean age 75 years and mean CHA2DS2-VASc score 4, were analyzed. Thirty-one patients randomized to control and twenty-nine to the treatment group. Majority of cases in each group were isolated CABG. No perioperative complications related to the treatment procedure, need for permanent pacemaker, or mortality occurred. The in-hospital incidence of POAF was 55% (17/31) in the control group and 7% (2/29) in the treatment group. (p<0.001) The control group had a significantly higher requirement for antiarrhythmic medications at discharge, 45% (14/31) vs 7% (2/29) in the treatment group (p<0.001). CONCLUSIONS: Prophylactic radiofrequency isolation of the pulmonary veins with left atrial appendage amputation, during the primary cardiac surgical operation, reduced the incidence of POAF in patients 70 years and older with no history of atrial arrhythmias.

Del Nido Cardioplegia in Ascending Aortic Surgery.

Del Nido cardioplegia offers equivalent myocardial protection and clinical outcomes to blood cardioplegia in adult isolated CABG and valve patients, but the safety and efficacy of del Nido in complex cases with prolonged aortic cross-clamp times is still unknown. 443 patients at our center underwent replacement of the ascending aorta using either del Nido (n = 182) or blood (n = 261) cardioplegia. Two surgeons used del Nido exclusively and 6 used blood exclusively over the study period. Propensity matching of preoperative characteristics yielded 172 well matched pairs. Emergency and reoperative cases were included. Clinical data were extracted from our local database. Troponin levels were drawn at 12 hours postop in all patients. Rates of perioperative mortality (4.7% vs 5.2%), stroke (5.8% vs 7.0%), renal failure (11.6% vs 12.2%), atrial fibrillation (36.0% vs 31.4%), intra-aortic balloon pump insertion (2.3% vs1.2%), and extra corporeal membrane oxygenation use (4.7% vs 4.1%) did not differ between blood and del Nido groups. Postop Troponin T levels were 0.50[0.35, 0.86] ng/mL and 0.40[0.20, 0.70] ng/mL for blood and del Nido, respectively (P < 0.0001). Postop echocardiography was available in 333 of 344 (96.8%) patients, and there was no difference in change in EF from pre- to postop between blood 0.0[-6.0, 5.0]% and del Nido 0.0 [-6.0, 3.5]% (P = 0.201). Subgroup analysis of patients with aortic cross-clamp time greater than 180 minutes (blood = 77, del Nido = 27) revealed no difference in troponins, ejection fraction, or clinical outcomes. Five-year survival was 85.9[76.8, 91.7]% and 79.8[71.2, 86.1]% for blood and del Nido, respectively (P = 0.151). In ascending aortic surgery with prolonged operative times, no differences were observed in myocardial protection or clinical outcomes with the use of del Nido cardioplegia compared to blood cardioplegia.

Physician Radiation Exposure During Endomyocardial Biopsy and Right Heart Catheterization.

BACKGROUND: Cardiologists performing coronary angiography (CA) and percutaneous coronary intervention (PCI) are at risk of health problems related to chronic occupational radiation exposure. Unlike during CA and PCI, physician radiation exposure during right heart catheterization (RHC) and endomyocardial biopsy (EMB) has not been adequately studied. The objective of this study was to assess physicians' radiation doses during RHC with and without EMB and compare them to those of CA and PCI. METHODS: Procedural head-level physician radiation doses were collected by real-time dosimeters. Radiation-dose metrics (fluoroscopy time, air kerma [AK] and dose area product [DAP]), and physician-level radiation doses were compared among RHC, RHC with EMB, CA, and PCI. RESULTS: Included in the study were 351 cardiac catheterization procedures. Of these, 36 (10.3%) were RHC, 42 (12%) RHC with EMB, 156 (44.4%) CA, and 117 (33.3%) PCI. RHC with EMB and CA had similar fluoroscopy time. AK and DAP were progressively higher for RHC, RHC with EMB, CA, and PCI. Head-level physician radiation doses were similar for RHC with EMB vs CA (P = 0.07). When physicians' radiation doses were normalized to DAP, RHC and RHC with EMB had the highest doses. CONCLUSION: Physicians' head-level radiation doses during RHC with EMB were similar to those of CA. After normalizing to DAP, RHC and RHC with EMB were associated with significantly higher physician radiation doses than CA or PCI. These observations suggest that additional protective measures should be undertaken to decrease physicians' radiation exposure during RHC and, in particular, RHC with EMB.

Dissection of transcriptome dysregulation and immune characterization in women with germline BRCA1 mutation at single-cell resolution.

BACKGROUND: High-grade serous carcinoma (HGSC) is the most frequent and lethal type of ovarian cancer. It has been proposed that tubal secretory cells are the origin of ovarian HGSC in women with familial BRCA1/2 mutations. However, the molecular changes underlying malignant transformation remain unknown. METHOD: We performed single-cell RNA and T cell receptor sequencing of tubal fimbriated ends from 3 BRCA1 germline mutation carriers (BRCA1 carriers) and 3 normal controls with no high-risk history (non-BRCA1 carriers). RESULTS: Exploring the transcriptomes of 19,008 cells, predominantly from BRCA1+ samples, we identified 5 major cell populations in the fallopian tubal mucosae. The secretory cells of BRCA1+ samples had differentially expressed genes involved in tumor growth and regulation, chemokine signaling, and antigen presentation compared to the wild-type BRCA1 controls. There are several novel findings in this study. First, a subset of the fallopian tubal secretory cells from one BRCA1 carrier exhibited an epithelial-to-mesenchymal transition (EMT) phenotype, which was also present in the mucosal fibroblasts. Second, we identified a previously unreported phenotypic split of the EMT secretory cells with distinct evolutionary endpoints. Third, we observed increased clonal expansion among the CD8+ T cell population from BRCA1+ carriers. Among those clonally expanded CD8+ T cells, PD-1 was significantly increased in tubal mucosae of BRCA1+ patients compared with that of normal controls, indicating that T cell exhaustion may occur before the development of any premalignant or malignant lesions. CONCLUSION: These results indicate that EMT and immune evasion in normal-looking tubal mucosae may represent early events leading to the development of HGSC in women with BRCA1 germline mutation. Our findings provide a probable molecular mechanism explaining why some, but not all, women with BRCA1 germline mutation present with early development and rapid dissemination of HGSC.

hiPSC-derived bone marrow milieu identifies a clinically actionable driver of niche-mediated treatment resistance in leukemia.

Leukemia cells re-program their microenvironment to augment blast proliferation and enhance treatment resistance. Means of clinically targeting such niche-driven treatment resistance remain ambiguous. We develop human induced pluripotent stem cell (hiPSC)-engineered niches to reveal druggable cancer-niche dependencies. We reveal that mesenchymal (iMSC) and vascular niche-like (iANG) hiPSC-derived cells support ex vivo proliferation of patient-derived leukemia cells, affect dormancy, and mediate treatment resistance. iMSCs protect dormant and cycling blasts against dexamethasone, while iANGs protect only dormant blasts. Leukemia proliferation and protection from dexamethasone-induced apoptosis is dependent on cancer-niche interactions mediated by CDH2. Consequently, we test CDH2 antagonist ADH-1 (previously in Phase I/II trials for solid tumors) in a very aggressive patient-derived xenograft leukemia mouse model. ADH-1 shows high in vivo efficacy; ADH-1/dexamethasone combination is superior to dexamethasone alone, with no ADH-1-conferred additional toxicity. These findings provide a proof-of-concept starting point to develop improved, potentially safer therapeutics targeting niche-mediated cancer dependencies in blood cancers.