Klebsiella pneumoniae manipulates human macrophages to acquire iron.

Background: Klebsiella pneumoniae (KP) is a major cause of hospital-acquired infections, such as pneumonia. Moreover, it is classified as a pathogen of concern due to sprawling anti-microbial resistance. During infection, the gram-negative pathogen is capable of establishing an intracellular niche in macrophages by altering cellular metabolism. One factor critically affecting the host-pathogen interaction is the availability of essential nutrients, like iron, which is required for KP to proliferate but which also modulates anti-microbial immune effector pathways. We hypothesized, that KP manipulates macrophage iron homeostasis to acquire this crucial nutrient for sustained proliferation. Methods: We applied an in-vitro infection model, in which human macrophage-like PMA-differentiated THP1 cells were infected with KP (strain ATCC 43816). During a 24-h course of infection, we quantified the number of intracellular bacteria via serial plating of cell lysates and evaluated the effects of different stimuli on intracellular bacterial numbers and iron acquisition. Furthermore, we analyzed host and pathogen specific gene and protein expression of key iron metabolism molecules. Results: Viable bacteria are recovered from macrophage cell lysates during the course of infection, indicative of persistence of bacteria within host cells and inefficient pathogen clearing by macrophages. Strikingly, following KP infection macrophages strongly induce the expression of the main cellular iron importer transferrin-receptor-1 (TFR1). Accordingly, intracellular KP proliferation is further augmented by the addition of iron loaded transferrin. The induction of TFR1 is mediated via the STAT-6-IL-10 axis, and pharmacological inhibition of this pathway reduces macrophage iron uptake, elicits bacterial iron starvation, and decreases bacterial survival. Conclusion: Our results suggest, that KP manipulates macrophage iron metabolism to acquire iron once confined inside the host cell and enforces intracellular bacterial persistence. This is facilitated by microbial mediated induction of TFR1 via the STAT-6-IL-10 axis. Mechanistic insights into immune metabolism will provide opportunities for the development of novel antimicrobial therapies.

The impact of anthracyclines in intermediate and high-risk HER2-negative early breast cancer-a pooled analysis of the randomised clinical trials PlanB and SUCCESS C.

BACKGROUND: Anthracycline/cyclophosphamide-taxane-containing chemotherapy (AC-T) is the standard of care in the adjuvant treatment of HER2-negative early breast cancer (EBC), but recent studies suggest omission of anthracyclines for reduced toxicity without compromising efficacy. METHODS: Based on individual patient data (n = 5924) pooled from the randomised Phase III trials PlanB and SUCCESS C, we compared disease-free survival (DFS) and overall survival (OS) between intermediate to high-risk HER2-negative EBC-patients treated with either six cycles of docetaxel/cyclophosphamide (TC6) or an AC-T regime using univariable and adjusted multivariable Cox regression models. RESULTS: AC-T conferred no significant DFS or OS advantage in univariable (DFS: hazard ratio (HR) for TC vs. AT 1.05, 95% confidence interval (CI): 0.89-1.24, P = 0.57; OS: HR 1.00, 95% CI: 0.80-1.26, P = 1.00) and adjusted multivariable analysis (DFS: HR 1.01, 95% CI: 0.86-1.19, P = 0.91; OS: HR 0.97, 95% CI: 0.77-1.22, P = 0.79). Patients receiving TC6 had significantly fewer grade 3-4 adverse events. Exploratory subgroup analysis showed that AC-T was associated with significantly better DFS and OS in pN2/3 patients, specifically in those with lobular histology. CONCLUSION: For most patients with HER2-negative EBC, AC-T is not associated with a survival benefit compared to TC6. However, patients with lobular pN2/pN3 tumours seem to benefit from anthracycline-containing chemotherapy.

Conducting Pre-deployment Training in Honduras: The 240th Forward Resuscitative Surgical Team Experience.

INTRODUCTION: Since January 2002, pre-deployment training of forward resuscitative and surgical units has taken place at the U.S. Army Trauma Training Center (ATTC) in Miami, FL. In June 2019, the 240th Forward Resuscitative Surgical Team (FRST) conducted the first pre-deployment Surgical Readiness Training Exercise (SURGRETE) in San Pedro Sula, Honduras, to allow the team to rehearse in a resource-constrained environment more similar to that expected on deployment. The purpose of this study is to describe and compare the pre-deployment training experiences of the 240th FRST during their SURGRETE in Honduras and ATTC rotation in Miami, FL. MATERIALS AND METHODS: A descriptive analysis of prospectively collected data was performed for surgical cases, trauma resuscitations, and nonsurgical procedures by the 240th FRST over a 2-week SURGRETE in Honduras and 2-week ATTC rotation in Miami, FL. Items accomplished within the Individual Critical Task Lists (ICTLs) of key clinical providers on the team (general surgeon, orthopedic surgeon, emergency medicine physician, and Certified Registered Nurse Anesthetist) were identified and compared to those accomplished at the ATTC. RESULTS: During the SURGRETE in Honduras, 64 surgical cases, 1 trauma resuscitation, 2 Advanced Cardiac Life Support codes, and 213 nonsurgical procedures were performed collectively by the team. During ATTC rotation, the team performed a combined total of 10 surgical cases, 6 trauma resuscitations, and 56 nonsurgical procedures. For each key clinical provider, more of their assigned ICTLs were conducted during the Honduras SURGRETE than during ATTC rotation. The ATTC, however, offered more cases of acute life-threatening trauma. CONCLUSION: Appropriately planned SURGRETEs can provide a concentrated case volume in a resource-constrained setting and challenge the team to consider definitive management algorithms. The cases performed may not necessarily reflect the type and acuity of operations performed in a deployed environment; however, they facilitate repetition of basic skills, team cohesion, and cross-training. The SURGRETE experience could be improved by locating a facility with a trauma-dominant patient population that allows increased autonomy of U.S. physicians.

Contemporary Trends in Physician Utilization Rates of CEA and CAS for Asymptomatic Carotid Stenosis among Medicare Beneficiaries.

BACKGROUND: Carotid revascularization for asymptomatic carotid artery stenosis (ACAS) has become increasingly controversial in the past few decades as the best medical therapy has improved. The aim of this study was to assess and define contemporary trends in the rate of carotid revascularization procedures for ACAS in the United States and to characterize outlier physicians performing a higher rate of asymptomatic revascularization compared to their peers. METHODS: We used 100% Medicare fee-for-service claims to identify all patients who were newly diagnosed with ACAS between 01/2011-06/2018. Patients with symptomatic carotid artery stenosis, those with prior carotid revascularization, and surgeons who performed ≤10 CEAs during the study period were excluded. We used a hierarchical multivariable logistic regression model to evaluate patient and physician characteristics associated with undergoing a carotid endarterectomy or carotid artery stent procedure within 3 months after the initial diagnosis of ACAS. We also assessed temporal trends in carotid revascularization rates over time using the Cochran-Armitage Trend Test. RESULTS: Overall, 795,512 patients (median age 73.9 years, 50.9% male, 87.6% white) had a first-time diagnosis of ACAS during the study period, of which 23,481 (3.0%) underwent carotid revascularization within 3 months. There was a significant decline in overall carotid artery revascularization rates over time (2011: 3.2% vs. 2018: 2.1%; P < 0.001). The median and mean physician-specific carotid revascularization rates were 2.0% (IQR 0.0%-6.3%) and 4.7% ± 7.1%, respectively. Three-hundred and fifty physicians (5.2%) had carotid revascularization rates ≥19%, which was more than 2 standard deviations above the mean. After adjusting for patient-level characteristics, physician-level variables associated with carotid revascularization for newly diagnosed ACAS included male sex (adjusted OR 1.59, 95% CI 1.35-1.89), more years in practice (≥31 vs. <10 years, aOR 1.64, 95% CI 1.32-2.04), rural practice location (aOR 1.34, 95% CI 1.18-1.52), Southern region practice location (versus Northeast, aOR 1.54, 95% CI 1.39-1.69), and lower volume of ACAS patients (lower versus upper tertile, aOR 2.62, 95% CI 2.39-2.89). Cardiothoracic surgeons had a 1.52-fold higher odds of carotid revascularization compared to vascular surgeons (95% CI 1.36-1.68), whereas cardiologists and radiologists had lower intervention rates (both, P < 0.05). CONCLUSIONS: The current early revascularization rate for newly diagnosed ACAS is <5% among proceduralists in the United States, and has been decreasing steadily since 2014. There are particular physician-level characteristics that are associated with higher rates of carotid revascularization that cannot be fully contextualized without high-level contemporary outcomes data to guide decision making in ACAS.

Differential impact of prognostic parameters in hormone receptor-positive lobular breast cancer.

BACKGROUND: Invasive lobular breast cancer (BC) is the second most common BC subtype. Prognostic parameters (tumor classification, lymph node status, histologic grade, Oncotype DX recurrence score [RS], progesterone receptor status, and Ki67 index) were retrospectively studied in a large, prospective clinical trial encompassing 2585 patients who had hormone receptor-positive early BC (the West German Study Group PlanB trial). METHODS: BCs were centrally reviewed and classified as lobular (n = 353; 14%) or nonlobular (n = 2232; 86%). The median follow-up was 60 months. Five-year disease-free survival (DFS) estimates were obtained using the Kaplan-Meier method. Prognostic parameters were evaluated using Cox proportional hazard models. RESULTS: Lobular BC was associated with higher tumor classification, higher lymph node status, lower histologic grade, lower Ki67 index, and low or intermediate RS. The prevalence of high RS (RS range, 26-100) was 3-fold lower in patients who had lobular BC compared with those who had nonlobular BC (8% vs 24%; P < .001). However, 5-year DFS estimates for lobular and nonlobular BC were similar (92.1% and 92.3%, respectively; P = .673). In multivariate analyses, prognostic parameters for DFS in lobular BC included grade 3 (hazard ratio, 5.06; 95% CI, 1.91-13.39) and a pathologic lymph node status (pN) of pN3 (hazard ratio, 12.16; 95% CI, 3.87-38.24), but not RS. By contrast, prognostic parameters in nonlobular BC included grade 3 (hazard ratio, 1.65; 95% CI, 1.11-2.44), pN3 (hazard ratio, 3.68; 95% CI, 1.60-8.46), and high RS (hazard ratio, 2.49; 95% CI, 1.69-3.68). CONCLUSIONS: Lobular BC is associated with low and intermediate RS, although 5-year DFS is similar to that of nonlobular BC. The effect of the RS in lobular BC appears to be distinct from that in nonlobular BC. For risk assessment, the RS needs to be complemented by clinicopathologic parameters for therapy decision making.

Association of TILs with clinical parameters, Recurrence Score® results, and prognosis in patients with early HER2-negative breast cancer (BC)-a translational analysis of the prospective WSG PlanB trial.

BACKGROUND: The presence of tumor-infiltrating lymphocytes has been associated with prognosis and chemotherapy response, particularly in high-risk breast cancer subtypes. There is limited data so far as to (i) how tumor-infiltrating lymphocyte (TIL) measurements correlate with genomic measurements such as the Oncotype DX Recurrence Score® and (ii) whether the survival impact of TIL measurements varies according to different adjuvant systemic therapies. METHODS: The WSG PlanB trial compared an anthracycline-free chemotherapy regimen (6x docetaxel/cyclophosphamide, TC) to an anthracycline-taxane sequence (4xEC followed by 4x docetaxel) in patients with intermediate-risk, HER2-negative early breast cancer (EBC). Patients with HR-positive HER2-negative EBC were further stratified to receive endocrine therapy alone vs. chemotherapy followed by endocrine therapy based on Recurrence Score results and nodal status. In this analysis, three independent observers quantified and categorized the presence of TILs among tumor samples from patients in PlanB. TIL measurements were correlated with clinical/pathological parameters and treatment outcome overall and according to the treatment arm. RESULTS: Disease-free survival (DFS) rates were significantly better (p = .04) in HR-negative patients with high vs. intermediate TIL levels and were higher in low vs. intermediate TIL patients, however with borderline significance only (p = .06). There were no significant differences among TIL categories in HR+ patients. High RS categories, HR-negative status, and high KI67 were independently and significantly associated with high TIL categories. There was no significant impact of TIL category on DFS in patients treated by endocrine therapy only; however, in patients receiving chemotherapy, DFS in the intermediate TIL category was lower than that in the other categories. CONCLUSION: Although the presence of high TILs is associated with negative prognostic parameters such as high KI67 and HR-negative status among patients with HR-positive HER2-negative EBC, patients with high TILs show a favorable 5-year DFS in both HR-positive/HER2-negative and triple-negative breast cancer.

West German Study PlanB Trial: Adjuvant Four Cycles of Epirubicin and Cyclophosphamide Plus Docetaxel Versus Six Cycles of Docetaxel and Cyclophosphamide in HER2-Negative Early Breast Cancer.

PURPOSE: The West German Study Group PlanB trial evaluated an anthracycline-free chemotherapy standard (six cycles of docetaxel and cyclophosphamide [TC]) in the routine treatment of human epidermal growth factor receptor 2-negative early breast cancer (EBC). PATIENTS AND METHODS: Patients with pT1 to pT4c, all pN+, and pN0/high-risk EBC were eligible. High-risk pN0 was defined by one or more of the following: pT greater than 2, grade 2 to 3, high urokinase-type plasminogen activator/plasminogen activator inhibitor-1, hormone receptor (HR) negativity, and less than 35 years of age. After an early amendment, all HR-positive tumors underwent recurrence score (RS) testing, with chemotherapy omission recommended in RS less than or equal to 11 pN0 to pN1 disease. Patients were randomly assigned to four cycles of epirubicin (E)90/cyclophoshamide (C)600 followed by four cycles of docetaxel (T)100 or six cycles of T75C600 (administered once every 3 weeks). The primary end point was disease-free survival (DFS); secondary end points were overall survival (OS) and safety. The protocol specified P = .05 for a noninferiority margin of 4.4% for all patients combined. RESULTS: Of the 3,198 registered patients, 348 (RS ≤ 11) omitted chemotherapy, and 401 were not randomly assigned. The intention-to-treat population included 2,449 patients (1,227 EC-T v 1,222 TC: postmenopausal, 62.2% v 60.8%; pN0, 58.2% v 59.5%; pT1, 57.6% v 52.3%; HR positive, 81.4% v 82.2%; RS greater than 25 [in HR-positive patients], 26.2% v 27.5%). Within the safety population (1,167 v 1,178 patients), 87.5% v 93.0% completed therapy. After a 60-month median follow-up, 5-year outcomes were similar in the EC-T and TC arms (DFS, 89.6% [95% CI, 87.9% to 91.5%] v 89.9% [95% CI, 88.1% to 91.8%]; OS, 94.5% [95% CI, 93.1% to 95.9%] v 94.7% [95% CI, 93.3% to 96.1%]). The DFS difference was within the noninferiority margin of the original trial design. Five treatment-related deaths were reported for TC (one for EC-T), despite a trend toward more-severe adverse events in the latter. Interaction analysis revealed no predictive trends with respect to key factors, including triple-negative, luminal A/B-like, pN, age, and RS status. CONCLUSION: In the West German Study Group PlanB trial, 5-year outcomes for TC and EC-T were equally excellent. Six cycles of TC is an effective/safe option in human epidermal growth factor receptor 2-negative EBC with pN0 high genomic risk or pN1 EBC with genomically intermediate- to high-risk disease.

Correction to: Reducing chemotherapy use in clinically high-risk, genomically low-risk pN0 and pN1 early breast cancer patients: five-year data from the prospective, randomised phase 3 West German Study Group (WSG) PlanB trial.

The article Reducing chemotherapy use in clinically high-risk, genomically low-risk pN0 and pN1 early breast cancer patients: five-year data from the prospective, randomised phase 3 West German Study Group (WSG) PlanB trial, written by Ulrike Nitz, Oleg Gluz, Matthias Christgen, Ronald E. Kates, Michael Clemens, Wolfram Malter, Benno Nuding, Bahriye Aktas, Sherko Kuemmel, Toralf Reimer, Andrea Stefek, Fatemeh Lorenz-Salehi, Petra Krabisch, Marianne Just, Doris Augustin, Cornelia Liedtke, Calvin Chao, Steven Shak, Rachel Wuerstlein, Hans H. Kreipe, Nadia Harbeck, was originally published electronically on the publisher's internet portal (currently SpringerLink) on June 29, 2017 without open access.With the author(s)' decision to opt for Open Choice the copyright of the article changed on January 6, 2019 to © The Author(s) 2017 and the article is forthwith distributed under the terms of the Creative Commons Attribution-NonCommercial 4.0 International License ( http://creativecommons.org/licenses/by-nc/4.0/ ), which permits any noncommercial use, duplication, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, a link is provided to the Creative Commons license and any changes made are indicated. The original article has been corrected.

Recurrent bacteremia: A 10-year retrospective study in combat-related burn casualties.

INTRODUCTION: Surviving the first episode of bacteremia predisposes burn casualties to its recurrence. Herein, we investigate the incidence, mortality, bacteriology, and source of infection of recurrent bacteremia in military burn casualties admitted to the U.S. Army Institute of Surgical Research Burn Center over a 10year period. METHODS: Bacteremia was defined as the growth of Gram-positive or Gram-negative organisms in a blood culture that excluded probable skin contaminants. Recurrent bacteremia was defined as a subsequent episode of bacteremia ≥7 days after the first episode. Polymicrobial bacteremia was the presence of more than one pathogen in the same blood culture. Bacteremia was attributed to UTI, pneumonia, or wound sepsis. All other bacteremias were considered non-attributable bloodstream infections. Univariate and multivariate analyses determined factors predictive of clinical outcome. RESULTS: Out of 952 combat-related burn casualties screened, 166 cases were identified; 63% (non-recurrent) and 37% (recurrent) with median time to recurrence of 20 days. Univariate and multivariate analysis showed that the mortality rate was two and nine-fold, respectively, higher with recurrent bacteremia. Univariate analysis found that except for urinary tract infection, large burn size (>20%), 3rd degree burns, increased injuiry severity, perineal burns, and mechanical ventilator days were independent factors predictive of recurrence of bacteremia as well as increased mortality in the recurrent bacteremia cohort. Acinetobacter baumannii complex (63%) was prevalent in the non-recurrent group, while Klebsiella pneumoniae (46% vs. 30%) and Pseudomonas aeruginosa (35% vs. 26%) were prevalent in recurrent bacteremia. Half of the recurrent bacteremia cases were polymicrobial, compared to 9% in non-recurrent bacteremia. Pneumonia was prevalent in non-recurrent bacteremia (38%) and a combination of pneumonia and wound sepsis (29%) in recurrent bacteremia casualties. CONCLUSIONS: Recurrent bacteremia increases mortality in military burn casualties. Additional research is needed to address and mitigate the underlying causes, thereby improving survival.

Using the injury severity score to adjust for comorbid trauma may be double counting burns: implications for burn research.

BACKGROUND: The injury severity score considers burn size and inhalation injury in estimating overall anatomical injury severity. Models that adjust for injury severity score in addition to total burn size and inhalation injury may therefore be double counting the risk from these individual burn characteristics, and obscuring (or overemphasizing) the contribution of risk from each source. The primary aim of this study was to compare differences in the estimated mortality risk of burn trauma using the traditional injury severity score (ISS) calculation and the non-burn injury severity score (NBISS) to examine how separating out the risk attributable to the burn injury versus other trauma changes the interpretation and clinical assessment. METHODS: Among U.S. casualties sustaining burns during combat operations in Iraq and Afghanistan from March 2003 to October 2013, we performed a retrospective cohort study. Unadjusted, adjusted, and weighted Cox proportional hazards models were performed to estimate the risk of age, burn injury severity, and non-burn injury severity on mortality. Weighted hazard ratios and adjusted survival curves were performed using non-parametric inverse probability weighting. RESULTS: Our final sample consisted of 902 service members with a mortality proportion of 5.7% (n=51). Adjusting for non-burn trauma with traditional ISS attenuated the risk of percent total body surface area burned (%TBSA) by 20% when modeled continuously [HR (95% CI): 1.27 (1.10-1.32) vs. 1.07 (0.99-1.15]. However, the adjusted model using NBISS only attenuated the associated mortality risk of burn size by 5% [HR (95% CI): 1.22 (1.12-1.34)] and had a similar model fit (AIC: 484.2 vs. 478.6). For the weighted Cox proportional hazards models, the risk from a large burn (%TBSA≥60) was also attenuated when adjusting for ISS [HR (95% CI): 2.80 (1.18-6.64)] compared to the model adjusting for NBISS [HR (95% CI): 5.63 (2.79-11.35)]. CONCLUSION: Our analysis comparing the use of traditional ISS and NBISS to measure comorbid non-burn trauma resulted in different interpretations for the effect of %TBSA on subsequent mortality. Our results suggest that the association of %TBSA with death can be obscured by the inclusion of traditional ISS. Therefore, we recommend using NBISS when constructing statistical models in this patient population.

Extracorporeal Filtration of Potassium in a Swine Model of Bilateral Hindlimb Ischemia-Reperfusion Injury With Severe Acute Hyperkalemia.

Introduction: Options for the treatment of hyperkalemia in the pre-hospital setting are limited, particularly in the context of natural disaster or during combat operations. Contemporary interventions require extensive resources and technical expertise. Here we examined the potential for a simple, field deployable bridge-dialysis as a countermeasure for acute hyperkalemia induced by prolonged ischemia-reperfusion. Methods: Twenty female swine were randomized into two experimental groups undergoing a 2-hour bilateral hindlimb ischemia-reperfusion injury. Subsequent to injury, hemoperfusion was performed in the presence (Column) and absence (Sham Control) of a high-affinity potassium-binding column (CytoSorbents, Monmouth Junction, NJ, USA). Serial blood gas and chemistries were sampled. Primary endpoint was changed in serum potassium concentrations post-injury and filtration. Results: Serum potassium was significantly elevated following ischemia-reperfusion injury in both groups (149% (12) and 150% (22), p < 0.05 vs respective baseline values). There were no differences observed between groups in respect to physiologic parameters; mean arterial pressure, heart rate, systemic vascular resistance, cardiac output, or central venous oxygenation. Filtration resulted in a significant relative decrease in potassium compared with controls after the first hour as determined by repeated measures two-way ANOVA (p < 0.0001) which continued through end of the study. Significant thrombocytopenia was observed in animals undergoing filtration with a mean reduction in platelets measured at T = 480 minutes (168 × 103µL, p < 0.0001 vs baseline). Conclusions: We demonstrate that serum potassium can be filtered via hemoperfusion utilizing a simple extracorporeal potassium-binding platform, though evolution of this technology will be required to achieve meaningful reduction of potassium in clinically significant hyperkalemia after trauma.

Immigration Restrictions as Active Labor Market Policy: Evidence from the Mexican Bracero Exclusion.

An important class of active labor market policy has received little impact evaluation: immigration barriers intended to raise wages and employment by shrinking labor supply. Theories of endogenous technical advance raise the possibility of limited or even perverse impact. We study a natural policy experiment: the exclusion of almost half a million Mexican 'bracero' farm workers from the United States to improve farm labor market conditions. With novel archival data we measure state-level exposure to exclusion, and model the labor-market effect in the absence of technical change. We reject such an effect and fail to reject a null effect.

Long-term trastuzumab (Herceptin®) treatment in a continuation study of patients with HER2-positive breast cancer or HER2-positive gastric cancer.

BACKGROUND: Trastuzumab (Herceptin® [H]) is the standard of care for HER2-positive locally advanced/metastatic breast cancer and gastric/gastroesophageal junction (GEJ) cancer. However, there is a paucity of data available on long-term H treatment of patients. The Rollover Protocol (ROP) Study was conducted to report safety data for patients with HER2-positive locally advanced/metastatic breast and gastric/GEJ cancer who have received long-term H therapy (≥ 5 years and ≥ 3 years for breast and gastric/GEJ cancer, respectively). METHODS: The ROP Study was a single-arm, multicenter, international continuation trial of H in patients who had previously completed a global Roche-sponsored trial with H therapy, had stable disease, and were receiving H at the end of the lead-in trial. Patients with chronic heart failure during the lead-in trial could be included following a risk-benefit analysis. The primary objectives were to provide H therapy to patients with HER2-overexpressing locally advanced/metastatic breast or gastric/GEJ cancer at the end of the lead-in study, and to follow the long-term outcomes and long-term overall safety in these patients. RESULTS: Twenty-five of 69 patients enrolled in the ROP Study received long-term H therapy (19 breast cancer and 6 gastric/GEJ cancer). The median duration of H treatment for patients with breast cancer was 8 years 7 months, and 5 years 2 months for patients with gastric/GEJ cancer. The cardiac status of the patients remained stable over time, with no serious cardiac adverse events or marked changes in left ventricular ejection fraction (LVEF). The median overall worst LVEF measurement was 57.0%, and no patients experienced an LVEF of < 45% (range 47-63%). There were no serious adverse events related to study treatment. CONCLUSIONS: These results suggest that H has an acceptable safety profile and was well tolerated in patients who received long-term H therapy (≥ 5 years and ≥ 3 years for breast and gastric/GEJ cancer, respectively). Further investigation and reporting of long-term H therapy would be valuable. TRIAL REGISTRATION: This study was retrospectively registered on March 24, 2016 with Clinicaltrials.gov, number NCT02721641 .

Initial Inoculation Concentration Does Not Affect Final Bacterial Colonization of In vitro Vascular Conduits.

BACKGROUND: Despite improved peri-operative care, prosthetic graft infections continue to cause substantial morbidity and mortality. Contemporary graft infection models have tested a conduit's infectability using varying concentrations without standardization. Using a static assay in vitro model, we sought to evaluate the impact of inoculation concentration on vascular conduit attachment. METHODS: The 2-hour and 24-hour attachment of Staphylococcus aureus TCH1516 and Pseudomonas aeruginosa PA01-UW were determined on polytetrafluoroethylene (PTFE), Dacron®, nitinol, cobalt chromium, and Viabahn® (W.L. Gore and Associates, Newark, DE) endoprotheses. Individually and in combination, concentrations at 104, 105, 106, 107, and 108 were tested on 2-mm sections of each graft. After each time interval, the prosthetics were rinsed to remove non-attached bacteria, sonicated to release the attached bacteria, spiral plated, and then analyzed for the attached concentration. RESULTS: After two hours, the higher initial inoculation concentration translated into a higher attachment percentage, but the mean attachment percentage was only 14.8% in the 108 group. Pseudomonas aeruginosa had the greatest mean attachment across all material and concentration groups. The sequence of attachment on the conduits followed a constant order: Dacron, PTFE, cobalt, nitinol, and Viabahn with no difference between Dacron and PTFE. Although there were still differences at the 24-hour mark, the median attachment at each concentration was greater than the highest initial concentration (108). CONCLUSIONS: Initial attachment percentage is poor consistently regardless of inoculation concentration, however, Staphylococcus aureus and Pseudomonas aeruginosa are still able to achieve full attachment after 24 hours. A concentration of less than 107 should be used in vascular graft infection models to ensure adequate bacterial attachment.

Rectal Trauma: Evidence-Based Practices.

The management of rectal trauma has often been lumped in with colon trauma when, in fact, it is a unique entity. The anatomic nature of the rectum (with its intra- and extraperitoneal segments) lends itself to unique circumstances when it comes to management and treatment. From the four Ds (debridement, drainage, diversion, and distal irrigation), the management of rectal trauma has made some strides in light of the experiences coming out of the recent conflicts overseas as well as some rethinking of dogma. This article will serve to review the anatomy and types of injuries associated with rectal trauma. A treatment algorithm will also be presented based on our current literature review. We will also address controversial points and attempt to give our opinion in an effort to provide an update on an age-old problem.

Comparison of Neoadjuvant Nab-Paclitaxel+Carboplatin vs Nab-Paclitaxel+Gemcitabine in Triple-Negative Breast Cancer: Randomized WSG-ADAPT-TN Trial Results.

Background: Pathological complete response (pCR) is associated with improved prognosis in triple-negative breast cancer (TNBC). The optimal chemotherapy regimen is unclear. Weekly nab-paclitaxel vs conventional paclitaxel or addition of carboplatin to anthracycline-taxane results in higher pCR rates with uncertain survival impact. We evaluated carboplatin vs gemcitabine with a nab-paclitaxel backbone as a short 12-week A-free regimen with a focus on early response. Methods: Patients with TNBC (estrogen receptor/progesterone receptor < 1%, human epidermal growth factor receptor 2-negative, cT1c-cT4c, cN0/+) were randomly assigned to A: nab-paclitaxel 125 mg/m2/gemcitabine 1000 mg/m2 d1,8 three times weekly (q3w); vs B: nab-paclitaxel 125 mg/m2/carboplatin AUC2 day 1,8 q3w. The trial was powered for a pCR (ypT0/is ypN0) comparison by therapy arm and early response (defined as Ki-67 decrease >30% or < 500 invasive tumor cells in the three-week serial biopsy). All statistical tests were two-sided. Results: A total of 336 patients were enrolled (48 centers, arms A/B: n = 182/154). The median age was 50 years. At baseline (A vs B), 62.6% and 62.9% had cT2-4c tumors; 86.8% and 90.9% completed therapy per protocol, respectively. pCR favored arm B (28.7%, 95% CI = 0.22 to 0.36, vs 45.9%, 95% CI = 0.38 to 0.54; 95% CI(dBA) = 6.2% to 27.9%, P = .002) and was lower in nonresponders than in early responders (19.5% vs 44.4%, P < .001) or in patients with unclassifiable early response (50.0%). The nab-paclitaxel/gemcitabine was associated with more frequent dose reductions (20.6% vs 11.9%, P = .04), treatment-related serious adverse events (11.1% vs 5.3%, P = .07), grade 3-4 infections (7.2% vs 2.6%, P = .07), and grade 3-4 ALAT elevations (11.7 vs 3.3%, P = .01). Conclusions: This first large randomized trial suggests high efficacy and excellent tolerability of a neoadjuvant nab-paclitaxel/carboplatin regimen, superior to nab-paclitaxel/gemcitabine in TNBC. De-escalation of further chemotherapy in patients with early pCR after a short anthracycline-free regimen is a promising field of future research. Early necrotic morphological changes and/or proliferation decrease after the first therapy cycle seem to be associated with subsequent pCR.

Successful Use of Nellix and Endovascular Aortic Sealing Technology for Treatment of Aortic Rupture in a Porcine Model.

BACKGROUND: Endovascular aortic sealing (EVAS) represents a recent transformation in approach for treatment of aortic aneurysms. Initial reporting has shown that EVAS using the Nellix device is safe with similar complication rates to standard endovascular aortic repair (EVAR). What remains unknown is how EVAS technology will behave in the ruptured setting. The purpose of this report is to discuss how EVAS system and endobag technology behave when deployed in a porcine model of aortic rupture. METHODS: A controlled left retroperitoneal rupture was created in 20 large swine. Following rupture, an EVAS system was deployed across the rupture site to seal the area. The primary end point was seal from ongoing hemorrhage. Other parameters were examined to include endobag extravasation, aortic wall pressure measurements and device behavior in a live tissue model. RESULTS: Of the EVAS systems used, 15 Nellix (Endologix, Irvine, CA) devices and 5 novel EVAS systems were used. Of the correctly deployed devices, 100% sealed the rupture (n = 19). One device was deployed above the rupture site, and seal was not achieved secondary to malpositioning. Endobag extravasation was seen with an average protrusion of 7.7 mm. No other areas of aortic injury were noted secondary to endobag trauma. Pressure recording from behind the endobag indicates loss of pulsatile flow to the aortic wall with polymer curing. CONCLUSIONS: Endovascular aortic sealing for rupture is feasible and performs well in a porcine model of aortic rupture. Polymer extravasation is seen and may be controllable by the implanter. Once the polymer has cured, pulsatile aortic wall pressure is no longer present. EVAS represents an emerging technology for treatment of aortic rupture.

Implication of 4E-BP1 protein dephosphorylation and accumulation in pancreatic cancer cell death induced by combined gemcitabine and TRAIL.

Pancreatic cancer cells show varying sensitivity to the anticancer effects of gemcitabine. However, as a chemotherapeutic agent, gemcitabine can cause intolerably high levels of toxicity and patients often develop resistance to the beneficial effects of this drug. Combination studies show that use of gemcitabine with the pro-apoptotic cytokine TRAIL can enhance the inhibition of survival and induction of apoptosis of pancreatic cancer cells. Additionally, following combination treatment there is a dramatic increase in the level of the hypophosphorylated form of the tumour suppressor protein 4E-BP1. This is associated with inhibition of mTOR activity, resulting from caspase-mediated cleavage of the Raptor and Rictor components of mTOR. Use of the pan-caspase inhibitor Z-VAD-FMK indicates that the increase in level of 4E-BP1 is also caspase-mediated. ShRNA-silencing of 4E-BP1 expression renders cells more resistant to cell death induced by the combination treatment. Since the levels of 4E-BP1 are relatively low in untreated pancreatic cancer cells these results suggest that combined therapy with gemcitabine and TRAIL could improve the responsiveness of tumours to treatment by elevating the expression of 4E-BP1.

Hyperkalemia in Combat Casualties: Implications for Delayed Evacuation.

OBJECTIVE: Fixed facilities and rapid global evacuation ensured that delayed complications of trauma, such as hyperkalemia, occurred late in the evacuation chain where renal replacement therapies were available. However, future conflicts or humanitarian disasters may involve prolonged evacuation times. We sought to quantify one potential risk of delayed evacuation by assessing hyperkalemia in combat casualties. METHODS: Retrospective study of military members admitted to intensive care units in Iraq and Afghanistan from February 1, 2002, to February 1, 2011. This study was approved by the U.S. Army Medical Research and Materiel Command Institutional Review Board. Demographics, injury severity score, burn injury, mechanism of injury, vital signs, creatinine, and potassium were collected. Logistic regression models were used to identify incidence and risk factors for hyperkalemia. RESULTS: Of 6,011 patient records, 1,472 had sufficient data to be included for analysis. Hyperkalemia occurred in 5.8% of patients. Those with hyperkalemia had higher injury severity scores, higher shock index, were more likely to have acute kidney injury, and were more likely to die. On multivariate analysis, acute kidney injury and shock index were significantly associated with the development of hyperkalemia. In a subgroup of patients with data on creatine kinase, rhabdomyolysis was associated with hyperkalemia in the univariate model, but was not significant after adjustment. CONCLUSION: Hyperkalemia occurred in 5.8% of patients in our cohort of critically injured combat casualties. The development of hyperkalemia was independently associated with acute kidney injury and shock index. In future conflicts, with prolonged evacuation times, mitigation strategies should be developed to treat hyperkalemia in casualties before arrival at definitive care.