The targeted SMAC mimetic SW IV-134 augments platinum-based chemotherapy in pre-clinical models of ovarian cancer.

BACKGROUND: Ovarian cancer is initially responsive to frontline chemotherapy. Unfortunately, it often recurs and becomes resistant to available therapies and the survival rate for advanced and recurrent ovarian cancer is unacceptably low. We thus hypothesized that it would be possible to achieve more durable treatment responses by combining cisplatin chemotherapy with SW IV-134, a cancer-targeted peptide mimetic and inducer of cell death. SW IV-134 is a recently developed small molecule conjugate linking a sigma-2 ligand with a peptide analog (mimetic) of the intrinsic death pathway activator SMAC (second-mitochondria activator of caspases). The sigma-2 receptor is overexpressed in ovarian cancer and the sigma-2 ligand portion of the conjugate facilitates cancer selectivity. The effector portion of the conjugate is expected to synergize with cisplatin chemotherapy and the cancer selectivity is expected to reduce putative off-target toxicities. METHODS: Ovarian cancer cell lines were treated with cisplatin alone, SW IV-134 alone and a combination of the two drugs. Treatment efficacy was determined using luminescent cell viability assays. Caspase-3/7, - 8 and - 9 activities were measured as complementary indicators of death pathway activation. Syngeneic mouse models and patient-derived xenograft (PDX) models of human ovarian cancer were studied for response to SW IV-134 and cisplatin monotherapy as well as combination therapy. Efficacy of the therapy was measured by tumor growth rate and survival as the primary readouts. Potential drug related toxicities were assessed at necropsy. RESULTS: The combination treatment was consistently superior in multiple cell lines when compared to the single agents in vitro. The expected mechanism of tumor cell death, such as caspase activation, was confirmed using luminescent and flow cytometry-based assay systems. Combination therapy proved to be superior in both syngeneic and PDX-based murine models of ovarian cancer. Most notably, combination therapy resulted in a complete resolution of established tumors in all study animals in a patient-derived xenograft model of ovarian cancer. CONCLUSIONS: The addition of SW IV-134 in combination with cisplatin chemotherapy represents a promising treatment option that warrants further pre-clinical development and evaluation as a therapy for women with advanced ovarian cancer.

Conjugation to a SMAC mimetic potentiates sigma-2 ligand induced tumor cell death in ovarian cancer.

BACKGROUND: Drug resistance is a significant problem in the treatment of ovarian cancer and can be caused by multiple mechanisms. Inhibition of apoptosis by the inhibitor of apoptosis proteins (IAPs) represents one such mechanism, and can be overcome by a mitochondrial protein called second mitochondria-derived activator of caspases (SMAC). We have previously shown that the ligands of sigma-2 receptors effectively induce tumor cell death. Additionally, because sigma-2 receptors are preferentially expressed in tumor cells, their ligands provide an effective mechanism for selective anti-cancer therapy. METHODS: In the current work, we have improved upon the previously described sigma-2 ligand SW43 by conjugating it to a pro-apoptotic small molecule SMAC mimetic SW IV-52, thus generating the novel cancer therapeutic SW IV-134. The new cancer drug was tested for receptor selectivity and tumor cell killing activity in vitro and in vivo. RESULTS: We have shown that SW IV-134 retained adequate sigma-2 receptor binding affinity in the context of the conjugate and potently induced cell death in ovarian cancer cells. The cell death induced by SW IV-134 was significantly greater than that observed with either SW43 or SW IV-52 alone and in combination. Furthermore, the intraperitoneal administration of SW IV-134 significantly reduced tumor burden and improved overall survival in a mouse xenograft model of ovarian cancer without causing significant adverse effects to normal tissues. Mechanistically, SW IV-134 induced degradation of cIAP-1 and cIAP-2 leading to NF-қB activation and TNFα-dependent cell death. CONCLUSIONS: Our findings suggest that coupling sigma-2 ligands to SMAC peptidomimetics enhances their effectiveness while maintaining the cancer selectivity. This encouraging proof-of-principle preclinical study supports further development of tumor-targeted small peptide mimetics via ligands to the sigma-2 receptor for future clinical applications.

Regional lymphadenectomy is indicated in the surgical treatment of pancreatic neuroendocrine tumors (PNETs).

OBJECTIVE: To explore the prognostic importance and preoperative predictors of lymph node metastasis in an effort to guide surgical decision making in patients with pancreatic neuroendocrine tumors (PNETs). BACKGROUND: PNETs are uncommon, and the natural history of the disease is not well described. As a result, there remains controversy regarding the optimal management of regional lymph nodes during resection of the primary tumor. METHODS: A retrospective review of a prospectively maintained database of patients who underwent surgery for locoregional PNET between 1994 and 2012 was performed. Logistic regression was used to identify predictors of nodal metastasis. Overall survival and disease-free survival were calculated using Kaplan-Meier method. Results were expressed as P values and odds ratio estimates, with 95% confidence intervals. RESULTS: One hundred thirty-six patients were identified, of whom 50 (38%) patients had nodal metastasis. The frequency of lymph node metastasis was higher for larger tumors [> 1.5 cm (odds ratio [OR] = 4.7)], tumors of the head as compared with body-tail of the pancreas (OR = 2.8), tumors with Ki-67 greater than 20% (OR = 6.7), and tumors with lymph vascular invasion (OR = 3.6) (P < 0.05). Median disease-free survival was lower for patients with nodal metastases (4.5 vs 14.6 years, P < 0.0001). CONCLUSIONS: Lymph node metastasis is predictive of poor outcomes in patients with PNETs. Preoperative variables are not able to reliably predict patients where the probability of lymph node involvement was less than 12%. These data support inclusion of regional lymphadenectomy in patients undergoing pancreatic resections for PNET.

Value of intraoperative neck margin analysis during Whipple for pancreatic adenocarcinoma: a multicenter analysis of 1399 patients.

INTRODUCTION: During pancreaticoduodenectomy (PD) for ductal adenocarcinoma, a frozen section (FS) neck margin is typically assessed, and if positive, additional pancreas is removed to achieve an R0 margin. We analyzed the association of this practice with improved overall survival (OS). METHODS: Patients who underwent PD for pancreatic ductal adenocarcinoma from January 2000 to August 2012 at 8 academic centers were classified by neck margin status as negative (R0) or microscopically positive (R1) on the basis of FS and permanent section (PS). Impact on OS of converting an FS-R1-neck margin to a PS-R0-neck margin by additional resection was assessed. RESULTS: A total of 1399 patients had FS neck margins analyzed. Median OS was 19.7 months. On FS, 152 patients (10.9%) were R1, and an additional 51 patients (3.6%) had false-negative FS-R0 margins. PS-R0-neck was achieved in 1196 patients (85.5%), 131 patients (9.3%) remained PS-R1, and 72 patients (5.1%) were converted from FS-R1-to-PS-R0 by additional resection. Median OS for PS-R0-neck patients was 21.1 months versus 13.7 months for PS-R1-neck patients (P < 0.001) and 11.9 months for FS-R1-to-PS-R0 patients (P < 0.001). Both FS-R1-to-PS-R0 and PS-R1-neck patients had larger tumors (P = 0.001), more perineural invasion (P = 0.02), and more node positivity (P = 0.08) than PS-R0-neck patients. On multivariate analysis controlling for adverse pathologic factors, FS-R1-to-PS-R0 conversion remained associated with significantly worse OS compared with PS-R0-neck patients (hazard ratio: 1.55; P = 0.009). CONCLUSIONS: For patients who undergo pancreaticoduodenectomy for pancreatic ductal adenocarcinoma, additional resection to achieve a negative neck margin after positive frozen section is not associated with improved OS.

The effect of appendectomy in future tubal infertility and ectopic pregnancy: a systematic review and meta-analysis.

BACKGROUND: Ruptured appendicitis has been implicated in causing scarring, which can lead to infertility and/or ectopic pregnancy. To assess the degree of association and the quality of evidence supporting the relation among appendectomy, female fertility outcomes, and ectopic pregnancy. METHODS: We systematically searched multiple electronic databases from inception through May 2013 for randomized trials and observational studies. Reviewers working independently and in duplicate extracted the study characteristics, the quality of the included studies, and the outcomes of interest. Random effects meta-analysis was used to pool the odds ratio (OR) from the included studies. RESULTS: Our meta-analysis based on seven observational studies provided evidence that previous appendectomy is not associated with increased incidence of infertility in women (OR = 1.03, 0.86-1.24, P = 0.71). This finding was further augmented by several noncomparative cohorts that discussed the same issue and reported nearly the same conclusion; however, these studies pointed toward putative negative impact of surgery for complicated appendicitis on fertility. Our second meta-analysis revealed the effect of appendectomy on ectopic pregnancy was found to be significant based on a pooled estimate from four studies (OR = 1.78, 95% confidence interval = 1.46-2.16, P < 0.0001). CONCLUSIONS: Appendectomy is significantly associated with an increased risk of ectopic pregnancy but not significantly associated with future infertility in women.

Reconsidering Fresh Frozen Plasma Availability to Reduce Blood Product Waste During Massive Transfusion Events in Trauma.

BACKGROUND: Within component therapy of massive transfusion protocol (MTP) in trauma, thawed plasma is particularly susceptible to expiring without use given its short 5-day shelf life. Optimizing the number of thawed products without compromising safety is important for hospital resource management. The goal is to examine thawed plasma utilization rates in trauma MTP events and optimize the MTP cooler content at our Level I trauma center. METHODS: Trauma MTP activations from 01/2019 to 12/2022 were retrospectively reviewed. During the study period, blood products were distributed in a 12:12:1 ratio of packed red blood cells (pRBC): plasma: platelets per cooler, with up to 4 additional units of low-titer, group O whole blood (LTOWB) available. The primary measure was percent return of unused, thawed plasma. RESULTS: There were 367 trauma MTP activations with a median (IQR) activation call-to-first cooler delivery time of 8 (6-10) minutes. 73.0% of thawed plasma was returned to the blood bank unused. In one third of MTP activations, all dispensed plasma was returned. The majority (74.1%) of patients required 6 or fewer units of plasma. In 81.5% of activations, 10 or fewer units of plasma and 10 or fewer units of pRBC were used. DISCUSSION: The majority of trauma MTP requirements may be accommodated with a reduced cooler content of 6 units pRBC, 6 units plasma, and 1 pheresis platelets, buffered by up to 4 units LTOWB (approximates 4 units of pRBC/4 units plasma), in conjunction with a sub-10min cooler delivery time. Follow-up longitudinal studies are needed.

Antithrombin III levels in critically ill surgical patients: do they correlate with VTE?

Objective: Antithrombin III (ATIII) deficiency may result from hereditary or acquired reduction in ATIII levels and is associated with an increase in venous thromboembolism (VTE) in the general population. VTE is a potentially preventable complication in the critically ill surgical patients. The objective of this study was to evaluate the relation between ATIII levels and VTE in surgical intensive care unit (SICU) patients. Methods: All patients admitted to the SICU from January 2017 to April 2018 who had ATIII levels drawn were included in the study. An ATIII level below 80% of normal was considered low. The rate of VTE during the same admission was compared among patients with normal and low levels of ATIII. Prolonged length of stay (LOS >10 days) and mortality were also measured. Results: Of the 227 patients included, 59.9% were male. The median age was 60 years. Overall, 66.9% of patients had low ATIII levels. Trauma patients had a higher rate of normal ATIII levels, whereas those weighing more than 100 kg had a higher rate of low ATIII levels. Patients with low ATIII levels had higher VTE rates compared with those with normal ATIII levels (28.9% vs. 16%, p=0.04). Patients with low ATIII levels also had prolonged LOS (76.3% vs. 60%, p=0.01) and increased mortality (21.7% vs. 6.7%, p<0.01). Trauma patients with VTE were more likely to have normal ATIII levels (38.5% in low ATIII cohort vs. 61.5% VTE in normal ATIII cohort, p<0.01). Conclusion: Critically ill surgical patients with low ATIII levels have higher incidence of VTE, longer LOS, and higher mortality. In contrast, critically ill trauma patients may have high incidence of VTE even with normal ATIII levels. Level of evidence: III.

Anastomotic leak rates after repair of mesenteric bucket-handle injuries: A multi-center retrospective cohort study.

BACKGROUND: Primary aim was to assess the relative risk (RR) of anastomotic leak (AL) in intestinal bucket-handle (BH) compared to non-BH injury. METHODS: Multi-center study comparing AL in BH from blunt trauma 2010-2021 compared to non-BH intestinal injuries. RR was calculated for small bowel and colonic injury using R. RESULTS: AL occurred in 20/385 (5.2%) of BH vs. 4/225 (1.8%) of non-BH small intestine injury. AL was diagnosed 11.6 ± 5.6 days from index operation in small intestine BH and 9.7 ± 4.3 days in colonic BH. Adjusted RR for AL was 2.32 [0.77-6.95] for small intestinal and 4.83 [1.47-15.89] for colonic injuries. AL increased infections, ventilator days, ICU & total length of stay, reoperation, and readmission rates, although mortality was unchanged. CONCLUSION: BH carries a significantly higher risk of AL, particularly in the colon, than other blunt intestinal injuries.

Rates and risk factors for anastomotic leak following blunt trauma-associated bucket handle intestinal injuries: a multicenter study.

Objectives: The risk factors for anastomotic leak (AL) after resection and primary anastomosis for traumatic bucket handle injury (BHI) have not been previously defined. This multicenter study was conducted to address this knowledge gap. Methods: This is a multicenter retrospective study on small intestine and colonic BHIs from blunt trauma between 2010 and 2021. Baseline patient characteristics, risk factors, presence of shock and transfusion, operative details, and clinical outcomes were compared using R. Results: Data on 395 subjects were submitted by 12 trauma centers, of whom 33 (8.1%) patients developed AL. Baseline details were similar, except for a higher proportion of patients in the AL group who had medical comorbidities such as diabetes, hypertension, and obesity (60.6% vs. 37.3%, p=0.015). AL had higher rates of surgical site infections (13.4% vs. 5.3%, p=0.004) and organ space infections (65.2% vs. 11.7%, p<0.001), along with higher readmission and reoperation rates (48.4% vs. 9.1%, p<0.001, and 39.4% vs. 11.6%, p<0.001, respectively). There was no difference in intensive care unit length of stay or mortality (p>0.05). More patients with AL were discharged with an ostomy (69.7% vs. 7.3%, p<0.001), and the mean duration until ostomy reversal was 5.85±3 months (range 2-12.4 months). The risk of AL significantly increased when the initial operation was a damage control procedure, after adjusting for age, sex, injury severity, presence of one or more comorbidities, shock, transfusion of >6 units of packed red blood cells, and site of injury (adjusted RR=2.32 (1.13, 5.17)), none of which were independent risk factors in themselves. Conclusion: Damage control surgery performed as the initial operation appears to double the risk of AL after intestinal BHI, even after controlling for other markers of injury severity. Level of evidence: III.

Correcting Coagulopathy With Fresh Frozen Plasma in the Surgical Intensive Care Unit: How Much Do We Need to Transfuse?

INTRODUCTION: Thromboelastography (TEG) is an assay that assesses the coagulation status. Patients with prolonged reaction time (R) require fresh frozen plasma (FFP); however, the volume required to correct the R time is unknown. We sought to quantify the volume required to correct the R time and calculate the response ratio in our surgical intensive care unit (SICU) to allow for targeted resuscitation. METHODS: Surgical intensive care unit patients between Aug 2017 and July 2019 with a prolonged initial R time and at least two TEG tests performed within 24 hours were included. The response ratio was defined as the change in the R time divided by the number of FFP units. High responders (response ratio >5 minutes/unit) were compared to low responders (response ratio ≤5 minutes/unit). RESULTS: Forty-six patients were included. While the mean response ratio was 5 minutes/unit, there was significant variation among patients. There were 28.0 (60.9%) low responders and 18.0 (39.1%) high responders. Low responders were more likely male (64.0% vs. 33.0%, P = .04), had a higher Acute Physiology and Chronic Health Evaluation (APACHE) IV score (42.0 vs. 27.0, P = .03), and a higher mortality rate (54.0% vs. 22.0%, P = .04). CONCLUSIONS: On average, one unit of FFP corrects the R time by 5 minutes; however, there was significant variation between high and low responders. Male patients with higher APACHE IV score are expected to be low responders with a higher mortality rate. These findings can guide FFP transfusion and provide additional prognostication.

Which Pelvic Fractures Are Associated With Extravasation on Angiography?

BACKGROUND: Bleeding from pelvic fractures can result in a high mortality rate unless quickly triaged by the trauma surgeon. Upon presentation, pelvic radiography may identify fractures that require angiography with possible embolization. We sought to address which fracture patterns seen on initial x-ray are associated with extravasation on angiography. METHODS: Data from a single institution retrospective review were collected on trauma patients admitted from 2011 to 2018 with pelvic fractures that required angiography. These fractures were identified by initial pelvic x-ray in the trauma bay and include anteroposterior compression (APC), lateral compression (LC), vertical shear (VS), and combined mechanism (CM) fractures, which are graded by severity. Fracture patterns high risk for bleeding, defined as APC II, APC III, LC III, VS, and CM, were compared to low-risk fracture patterns. RESULTS: Of the patients reviewed, 28 underwent pelvic angiography, 16 (57%) of which had extravasation. The difference in the incidence of extravasation between high and low-risk fracture patterns did not reach significance (36% vs 79%, P = .05). When comparing patients with acetabular fractures to those without, there was a significantly higher rate of extravasation associated with acetabular fractures (89% vs 42%, P value = .04), which were more likely to occur with LC I fractures (56% vs 11%, P = .02). CONCLUSION: Our data suggest that traditional pelvic fracture patterns may overestimate the presence of extravasation. Acetabular fractures had a high rate of extravasation, suggesting that these fractures should be considered for early angiography with possible embolization when clinically warranted.

Complications and Transfusions on Therapeutic Anticoagulation After Trauma.

INTRODUCTION: Trauma patients who develop indications for therapeutic anticoagulation (TAC) present a challenge due to concern for bleeding. Transfusion requirement has been described as a common complication of TAC after trauma but its clinical relevance is unclear. OBJECTIVE: Determine risk factors for and clinical outcomes associated with transfusion requirement on TAC after trauma. METHODS: All trauma patients admitted to an academic urban level I trauma center from January 2010 to August 2020 who received TAC were included in this retrospective cohort study. Data included injury characteristics; TAC indication and timing; transfusions; and interventions. Patients who required transfusion after TAC were compared to those who did not. RESULTS: Eighty-two patients were included. The most common reasons for TAC were deep vein thrombosis (67.1%) and pulmonary embolism (31.7%). Two (2.4%) patients developed gastrointestinal bleeding. One (1.2%) underwent endoscopic intervention. Two patients (4.9%) had intracranial hemorrhage progression. Blood transfusion after TAC initiation was required in 43.9% of patients. Patients who were transfused started TAC more quickly after traumatic injury (5.5 vs 10.0 days, P = .03), had fewer hospital-free days (54 vs 64 days, P < .01), ICU-free days (8.5 vs 16.5 days, P = .01), and higher mortality (13.9% vs 2.1%, P = .04). CONCLUSION: Transfusions are common after starting TAC in trauma patients. Requiring transfusion after starting TAC was associated with shorter time from injury to starting TAC, higher mortality, and fewer ICU and hospital-free days.

Overtransfusion of packed red blood cells during massive transfusion activation: a potential quality metric for trauma resuscitation.

Objectives: The goal of this study was to explore the incidence of overtransfusion in trauma patients requiring massive transfusion protocol (MTP) activation and identify modifiable risk factors. We hypothesized that overtransfusion is common after MTP activation. Methods: Patients admitted to a level I trauma center from July 2016 to December 2019 and who required MTP activation were selected. The primary outcome was overtransfusion, defined as a hemoglobin (Hg) ≥11 g/dL at 24 hours (±2 hours). A Cox regression model was used to identify independent risk factors for overtransfusion. Results: 140 patients met inclusion criteria. The median age was 39.0 years, with the majority (74.3%) being male. The median (IQR) Injury Severity Score (ISS) was 24.0 (58.0) and 38.4% had a penetrating mechanism. The median (IQR) admission Hg was 12.6 (11.7) g/dL. Overall, 71.4% of patients were overtransfused by the conclusion of MTP, 43.6% 24 hours later, and 29.5% at discharge. Overtransfusion did not correlate with the number of units of blood transfused nor with the duration of MTP. Overtransfused patients at 24 hours after the conclusion of MTP were significantly more likely to present with a penetrating injury (52.5% vs. 27.3%, p=0.003) and have a significantly lower ISS (median (IQR) 18.5 (44.0) vs. 26.0 (58.0), p=0.035.) In a Cox regression model, penetrating mechanism (adjusted HR (AHR): 2.93; adjusted p=0.004) and admission base excess (BE) (AHR: 1.15; adjusted p=0.001) were the only variables independently associated with overtransfusion. Conclusions: Overtransfusion of trauma patients requiring MTP activation is highly common, leading to overutilization of a limited resource. Penetrating trauma and BE may be modifiable risk factors that can help limit overtransfusion. Overtransfusion should be tracked as a data point by blood banks and trauma centers and be further studied as a potential quality metric for the resuscitation of massively transfused trauma patients. Level of evidence: III.

Clinical Characteristics Associated With Higher Enoxaparin Dosing Requirements for Venous Thromboembolism Prophylaxis in Trauma Patients.

INTRODUCTION: Enoxaparin dosed by an anti-Xa trough level is effective at reducing venous thromboembolism (VTE) in trauma patients. We identified the patient characteristics associated with higher enoxaparin dosing based on anti-Xa trough levels. METHODS: A retrospective review was conducted on trauma patients admitted between August 2014 and February 2018 who received enoxaparin dosed by the anti-Xa trough level. Patients who received enoxaparin < 50 mg every 12 hours were compared to those who required ≥ 50 mg every 12 hours. RESULTS: Of the 246 patients included, 32 (13.0%) required enoxaparin ≥ 50 mg every 12 hours to achieve the prophylactic trough level. Factors associated with a higher dose of enoxaparin were male (96.8% vs. 3.2%, P < .01), younger age (39.5 vs. 52.7 years, P < .01), higher creatinine clearance (CrCl) (125.9 vs. 93.7 mL/min, P < .01), higher body surface area (2 m2 vs. 1.8 m2, P < .01), and higher injury severity score (18.4 vs. 10.8, P < .01). Height, weight, and body mass index were not significant factors. On regression analysis, CrCl was the only independent predictor for higher enoxaparin dose. There was an increased deep venous thrombosis rate in the higher dose cohort (12.5% vs. 0, P < .01) but no significant differences in transfusion rates. CONCLUSION: Trauma patients who require higher enoxaparin doses to achieve prophylactic anti-Xa trough levels have a higher CrCl. Patients with high CrCl may benefit from an initial higher dose of enoxaparin to achieve a target anti-Xa level in a shorter time interval to decrease VTE risk.

Early Propranolol Is Associated With Lower Risk of Venous Thromboembolism After Traumatic Brain Injury.

BACKGROUND: Traumatic brain injury (TBI) results in an elaborate systemic cascade of secondary injury elicited in part by an intrinsic catecholamine response, which ultimately leads to changes in inflammation and coagulopathy. Attenuation of this catecholamine response with agents such as propranolol confers a survival advantage. The related impact of propranolol on venous thromboembolism (VTE) after TBI is largely unknown. STUDY DESIGN: A single institution retrospective review was conducted of all TBI patients requiring intensive care unit (ICU) admission with an injury severity scale (ISS) ≥ 25 from January 2013 to May 2015. Patients who received at least one dose of propranolol within 24 hours of admission (PROP) were compared to patients who did not receive any doses of propranolol (NPROP) during their hospitalization. RESULTS: Of the 131 patients analyzed, 31 (23.7%) patients received propranolol. The PROP cohort was more severely injured overall (ISS 29 vs 26.5, P = .02). While unadjusted VTE rates were similar (16.1% vs 19.0%, P = .72), the adjusted VTE rate was lower in the PROP cohort (AOR 0.20 (95% CI 0.04-0.97), adjusted P-value < .05). CONCLUSION: Propranolol use in TBI patients who have sustained critical injuries may mitigate the risk of VTE. The mechanism by which this outcome is achieved requires further investigation.

Characterizing the delays in adequate thromboprophylaxis after TBI.

BACKGROUND: We sought to compare enoxaparin dosing for venous thromboembolism (VTE) prophylaxis in trauma patients with and without traumatic brain injury (TBI) to better understand the time and dose required to reach target anti-Xa levels. Our hypothesis was that patients with TBI have significant delays in the initiation of adequate pharmacological prophylaxis and require a higher enoxaparin dose than currently recommended. METHODS: The medical records of trauma patients who received enoxaparin dosing based on anti-Xa trough levels between August 2014 and October 2016 were reviewed. Patients were included if their anti-Xa trough level reached the target range (0.1 IU/mL to 0.2 IU/mL). RESULTS: A total of 163 patients had anti-Xa levels within the target range of which 41 (25.2%) had TBI. Patients with TBI had longer delays before initiating enoxaparin (7.5 days vs. 1.5 days after admission, p<0.01) and were more likely to receive unfractionated heparin prior to enoxaparin (46.3% vs. 11.5%, p<0.01). Anti-Xa levels reached the target range later in patients with TBI (11 days vs. 5 days after admission, p<0.01). Enoxaparin 40 mg two times per day was the median dose required to reach the target anti-Xa levels for both cohorts. VTE rates were higher among patients with TBI (22.0% vs. 9.0%, p=0.03). Four patients (9.8%) had progression of their intracranial hemorrhage prior to receiving enoxaparin, although none progressed during enoxaparin administration. CONCLUSION: Among patients with TBI who reached target anti-Xa levels, 11 days after admission were required to reach a median enoxaparin dose of 40 mg two times per day. Unfractionated heparin was used as pharmacological prophylaxis in about half of these patients. The delay in reaching the target anti-Xa levels and the use of unfractionated heparin likely contribute to the higher VTE rate in patients with TBI. LEVEL OF EVIDENCE: Level III, therapeutic.

Which Trauma Patients Require Lower Enoxaparin Dosing for Venous Thromboembolism Prophylaxis?

Trauma patients have a high risk for venous thromboembolism (VTE) such that an increased enoxaparin dose is necessary to reduce related complications. Given that most trauma patients require an enoxaparin dose of at least 40 mg every 12 hours for VTE prophylaxis, we sought to identify which patients require enoxaparin 30 mg every 12 hours and hypothesized that both weight and low creatinine clearance (CrCl) would more likely determine enoxaparin dosing than age, body mass index (BMI), or body surface area (BSA). Single institution data were collected on trauma patients between August 2014 and February 2018 to compare trauma patients who required enoxaparin 30 mg to those who required ≥40 mg every 12 hours. Of the 245 patients included, 86 (35.1%) required enoxaparin at 30 mg to achieve the goal anti-factor Xa trough level. Factors associated with low dose enoxaparin were older age (59.6 vs. 46.2 years, P ≤ .01) and lower CrCl (81.5 mL/min vs. 93.7 mL/min, P ≤ .01). Weight, BSA, and BMI did not alter the dose of enoxaparin. A regression model determined that only CrCl predicted the need for low dose enoxaparin (adjusted odds ratio .982, 95% CI: .975-.990, P < .01). Although an initial dose of enoxaparin 40 mg is appropriate for most trauma patients, patients with low CrCl should receive 30 mg. Increased age and low weight were not associated with the need for a lower enoxaparin dose.

The Targeted SMAC Mimetic SW IV-134 is a strong enhancer of standard chemotherapy in pancreatic cancer.

BACKGROUND: Pancreatic cancer is a lethal malignancy that frequently acquires resistance to conventional chemotherapies often associated with overexpression of inhibitors of apoptosis proteins (IAPs). We have recently described a novel means to deliver second mitochondria-derived activator of caspases (SMAC) mimetics selectively to cancer cells employing the sigma-2 ligand/receptor interaction. The intrinsic death pathway agonist SMAC offers an excellent opportunity to counteract the anti-apoptotic activity of IAPs. SMAC mimetics have been used to sensitize several cancer types to chemotherapeutic agents but cancer-selective delivery and appropriate cellular localization have not yet been considered. In our current study, we tested the ability of the sigma-2/SMAC drug conjugate SW IV-134 to sensitize pancreatic cancer cells to gemcitabine. METHODS: Using the targeted SMAC mimetic SW IV-134, inhibition of the X-linked inhibitor of apoptosis proteins (XIAP) was induced pharmacologically and its impact on cell viability was studied alone and in combination with gemcitabine. Pathway analyses were performed by assessing caspase activation, PARP cleavage and membrane blebbing (Annexin-V), key components of apoptotic cell death. Single-agent treatment regimens were compared with combination therapy in a preclinical mouse model of pancreatic cancer. RESULTS: The sensitizing effect of XIAP interference toward gemcitabine was confirmed via pharmacological intervention using our recently designed, targeted SMAC mimetic SW IV-134 across a wide range of commonly used pancreatic cancer cell lines at concentrations where the individual drugs showed only minimal activity. On a mechanistic level, we identified involvement of key components of the apoptosis machinery during cell death execution. Furthermore, combination therapy proved superior in decreasing the tumor burden and extending the lives of the animals in a preclinical mouse model of pancreatic cancer. CONCLUSION: We believe that the strong sensitizing capacity of SW IV-134 in combination with clinically relevant doses of gemcitabine represents a promising treatment option that warrants clinical evaluation.

Conjugation to the sigma-2 ligand SV119 overcomes uptake blockade and converts dm-Erastin into a potent pancreatic cancer therapeutic.

Cancer-selective drug delivery is an important concept in improving treatment while minimizing off-site toxicities, and sigma-2 receptors, which are overexpressed in solid tumors, represent attractive pharmacologic targets. Select sigma-2 ligands have been shown to be rapidly internalized selectively into cancer cells while retaining the capacity to deliver small molecules as drug cargoes. We utilized the sigma-2-based drug delivery concept to convert Erastin, a clinically underperforming drug, into a potent pancreatic cancer therapeutic. The Erastin derivative des-methyl Erastin (dm-Erastin) was chemically linked to sigma-2 ligand SV119 to create SW V-49. Conjugation increased the killing capacity of dm-Erastin by nearly 35-fold in vitro and reduced the size of established tumors and doubled the median survival in syngeneic and patient-derived xenograft models when compared to non-targeted dm-Erastin. Mechanistic analyses demonstrated that cell death was associated with robust reactive oxygen species production and could be efficiently antagonized with antioxidants. Mass spectrometry was employed to demonstrate selective uptake into pancreatic cancer cells. Thus, targeted delivery of dm-Erastin via conjugation to the sigma-2 ligand SV119 produced efficient tumor control and prolonged animal survival with minimal off-target toxicities, and SW V-49 represents a promising new therapeutic with the potential to advance the fight against pancreatic cancer.

Intra-abdominal venous thrombosis after colectomy in pediatric patients with chronic ulcerative colitis: incidence, treatment, and outcomes.

PURPOSE: Children with chronic ulcerative colitis (CUC) are at increased risk for venous thromboembolism, especially after colectomy procedures. We aim to review our patients with CUC who underwent a colectomy and suffered intra-abdominal thrombosis; moreover we wanted to define thrombotic incidence and outcomes METHODS: In this is IRB approved retrospective study, we reviewed our patients who underwent colectomy for CUC from January 1999 to December 2011 for development of intra-abdominal thrombosis. RESULTS: Of 366 patients with CUC who underwent colectomy, 15 (4%) were diagnosed with a venous thromboembolism. All patients presented with acute abdominal pain. The locations of thrombus formation varied: 13 (87%) developed thrombi in the portal vein, 4 (27%) in the splenic vein, 2 (13%) in the superior mesenteric vein, 1 (7%) in the hepatic vein, and 1 (7%) in the hepatic artery. The mean number of post-operative days at diagnosis of thrombus was 38.7 days (range 3-180 days). Fourteen patients (93%) underwent anticoagulation for treatment. The mean number of days of anticoagulant therapy until documented resolution of thrombus on imaging was 96.3 days (range 14-364 days). All thrombi resolved with therapy. There was no mortality during follow-up. CONCLUSIONS: Four percent of our pediatric patients with chronic ulcerative colitis who underwent colectomy developed symptomatic intra-abdominal venous thromboembolism. 3 to 6 months of anticoagulant therapy is adequate treatment in almost all patients. Practitioners should have a high index of suspicion for intra-abdominal venous thrombus when these patients complain of abdominal pain postoperatively. Based on our experience, prophylactic anticoagulation should be strongly considered peri-operatively in this population.