Phase I/II Trial of Carboplatin, Nab-paclitaxel, and Pembrolizumab for Advanced Non-Small Cell Lung Cancer: Hoosier Cancer Research Network LUN13-175.

BACKGROUND: Combination chemotherapy and immunotherapy regimens have significantly improved survival for patients with previously untreated advanced non-small cell lung cancer (NSCLC). Improvements in overall survival (OS) in two separate pembrolizumab trials have demonstrated survival improvements over chemotherapy alone, regardless of PD-L1 status. The optimal chemotherapy backbone for combination with immunotherapy is unknown. We hypothesized nab-paclitaxel may be a well-suited platinum partner to use in combination with checkpoint inhibitor therapy for both adenocarcinoma and squamous histology and conducted a phase I/II trial to assess the efficacy of this regimen in advanced NSCLC. METHODS: Adult patients with previously untreated, stage IIIB/IV NSCLC (any histology) with an Eastern Cooperative Oncology Group performance status of 0-1, any PD-L1 expression, and no EGFR mutations or ALK translocations, received carboplatin area under the curve (AUC) 6 day 1, nab-paclitaxel 100 mg/m2 days 1, 8, 15, and pembrolizumab 200 mg day 1 q21 days for 4 cycles followed by maintenance pembrolizumab q3w. Co-primary endpoints were progression-free survival (PFS) and overall response rate (ORR). RESULTS: Forty-six evaluable patients enrolled, 14 in phase I and 32 in phase II, from June 2015 to July 2018 with a median duration of follow-up of 35.4 months. Median time from enrollment to data lock was 42 months. In the ITT population, the ORR was 35%, median PFS was 5.6 months (95% CI, 4.6-8.2), and median OS was 15.4 months (CI, 12.4-28.1). There were no statistical differences in PFS or OS by PD-L1 status. The 2- and 3-year landmark OS rates were 33% and 24%, respectively. CONCLUSION: Carboplatin, nab-paclitaxel, and pembrolizumab are a safe and effective regimen for patients with both squamous and nonsquamous NSCLC. Although this study did not meet the prespecified endpoints, the median and landmark OS results are consistent with durable benefit of this regimen as seen in phase III trials for first-line treatment of advanced NSCLC.

Clinical outcomes of hypomethylating agents plus Venetoclax as frontline treatment in patients 75 years and older with acute myeloid leukemia: Real-world data from eight US academic centers.

Venetoclax (VEN) combined with hypomethylating agents (HMAs) is the standard of care for the treatment of patients with newly diagnosed acute myeloid leukemia (AML) unfit for intensive chemotherapy. To date, real-world data published on HMAs plus VEN have been either single-center studies or using community-based electronic databases with limited details on mutational landscape, tolerability, and treatment patterns in elderly patients. Therefore, we conducted a multicenter retrospective study to assess the real-world experience of 204 elderly patients (≥75 years) with newly diagnosed AML treated with HMAs plus VEN from eight academic centers in the United States. Overall, 64 patients achieved complete remission (CR; 38%) and 43 CR with incomplete count recovery (CRi; 26%) for a CR/CRi rate of 64%, with a median duration of response of 14.2 months (95% CI: 9.43, 22.1). Among responders, 63 patients relapsed (59%) with median overall survival (OS) after relapse of 3.4 months (95% CI, 2.4, 6.7). Median OS for the entire population was 9.5 months (95% CI, 7.85-13.5), with OS significantly worse among patients with TP53-mutated AML (2.5 months) and improved in patients harboring NPM1, IDH1, and IDH2 mutations (13.5, 18.3, and 21.1 months, respectively). The 30-day and 60-day mortality rates were 9% and 19%, respectively. In conclusion, HMAs plus VEN yielded high response rates in elderly patients with newly diagnosed AML. The median OS was inferior to that reported in the VIALE-A trial. Outcomes are dismal after failure of HMAs plus VEN, representing an area of urgent unmet clinical need.

Repeated blood-brain barrier opening with an implantable ultrasound device for delivery of albumin-bound paclitaxel in patients with recurrent glioblastoma: a phase 1 trial.

BACKGROUND: Low-intensity pulsed ultrasound with concomitant administration of intravenous microbubbles (LIPU-MB) can be used to open the blood-brain barrier. We aimed to assess the safety and pharmacokinetics of LIPU-MB to enhance the delivery of albumin-bound paclitaxel to the peritumoural brain of patients with recurrent glioblastoma. METHODS: We conducted a dose-escalation phase 1 clinical trial in adults (aged ≥18 years) with recurrent glioblastoma, a tumour diameter of 70 mm or smaller, and a Karnofsky performance status of at least 70. A nine-emitter ultrasound device was implanted into a skull window after tumour resection. LIPU-MB with intravenous albumin-bound paclitaxel infusion was done every 3 weeks for up to six cycles. Six dose levels of albumin-bound paclitaxel (40 mg/m2, 80 mg/m2, 135 mg/m2, 175 mg/m2, 215 mg/m2, and 260 mg/m2) were evaluated. The primary endpoint was dose-limiting toxicity occurring during the first cycle of sonication and albumin-bound paclitaxel chemotherapy. Safety was assessed in all treated patients. Analyses were done in the per-protocol population. Blood-brain barrier opening was investigated by MRI before and after sonication. We also did pharmacokinetic analyses of LIPU-MB in a subgroup of patients from the current study and a subgroup of patients who received carboplatin as part of a similar trial (NCT03744026). This study is registered with ClinicalTrials.gov, NCT04528680, and a phase 2 trial is currently open for accrual. FINDINGS: 17 patients (nine men and eight women) were enrolled between Oct 29, 2020, and Feb 21, 2022. As of data cutoff on Sept 6, 2022, median follow-up was 11·89 months (IQR 11·12-12·78). One patient was treated per dose level of albumin-bound paclitaxel for levels 1 to 5 (40-215 mg/m2), and 12 patients were treated at dose level 6 (260 mg/m2). A total of 68 cycles of LIPU-MB-based blood-brain barrier opening were done (median 3 cycles per patient [range 2-6]). At a dose of 260 mg/m2, encephalopathy (grade 3) occurred in one (8%) of 12 patients during the first cycle (considered a dose-limiting toxicity), and in one other patient during the second cycle (grade 2). In both cases, the toxicity resolved and treatment continued at a lower dose of albumin-bound paclitaxel, with a dose of 175 mg/m2 in the case of the grade 3 encephalopathy, and to 215 mg/m2 in the case of the grade 2 encephalopathy. Grade 2 peripheral neuropathy was observed in one patient during the third cycle of 260 mg/m2 albumin-bound paclitaxel. No progressive neurological deficits attributed to LIPU-MB were observed. LIPU-MB-based blood-brain barrier opening was most commonly associated with immediate yet transient grade 1-2 headache (12 [71%] of 17 patients). The most common grade 3-4 treatment-emergent adverse events were neutropenia (eight [47%]), leukopenia (five [29%]), and hypertension (five [29%]). No treatment-related deaths occurred during the study. Imaging analysis showed blood-brain barrier opening in the brain regions targeted by LIPU-MB, which diminished over the first 1 h after sonication. Pharmacokinetic analyses showed that LIPU-MB led to increases in the mean brain parenchymal concentrations of albumin-bound paclitaxel (from 0·037 µM [95% CI 0·022-0·063] in non-sonicated brain to 0·139 µM [0·083-0·232] in sonicated brain [3·7-times increase], p<0·0001) and carboplatin (from 0·991 µM [0·562-1·747] in non-sonicated brain to 5·878 µM [3·462-9·980] µM in sonicated brain [5·9-times increase], p=0·0001). INTERPRETATION: LIPU-MB using a skull-implantable ultrasound device transiently opens the blood-brain barrier allowing for safe, repeated penetration of cytotoxic drugs into the brain. This study has prompted a subsequent phase 2 study combining LIPU-MB with albumin-bound paclitaxel plus carboplatin (NCT04528680), which is ongoing. FUNDING: National Institutes of Health and National Cancer Institute, Moceri Family Foundation, and the Panattoni family.

Combination of pembrolizumab and pelareorep promotes anti-tumour immunity in advanced pancreatic adenocarcinoma (PDAC).

BACKGROUND: We previously reported activity of pelareorep, pembrolizumab and chemotherapy. Patients developed new T-cell clones and increased peripheral T-cell clonality, leading to an inflamed tumour. To evaluate a chemotherapy-free regimen, this study assesses if pelareorep and pembrolizumab has efficacy by inducing anti-tumour immunological changes (NCT03723915). METHODS: PDAC patients who progressed after first-line therapy, received iv pelareorep induction with pembrolizumab every 21-days. Primary objective is overall response rate. Secondary objectives included evaluation of immunological changes within tumour and blood. RESULTS: Clinical benefit rate (CBR) was 42% amongst 12 patients. One patient achieved partial response (PR) and four stable disease (SD). Seven progressed, deemed non-responders (NR). VDAC1 expression in peripheral CD8+ T cells was higher at baseline in CBR than NR but decreased in CBR upon treatment. On-treatment peripheral CD4+ Treg levels decreased in CBR but not in NR. Analysis of tumour demonstrated PD-L1+ cells touching CD8+ T cells, and NK cells were more abundant post-treatment vs. baseline. A higher intensity of PD-L1 in tumour infiltrates at baseline, particularly in CBR vs. NR. Finally, higher levels of soluble (s)IDO, sLag3, sPD-1 observed at baseline among NR vs. CBR. CONCLUSION: Pelareorep and pembrolizumab showed modest efficacy in unselected patients, although potential immune and metabolic biomarkers were identified to warrant further evaluation.

Therapy-related myeloid neoplasms with normal karyotype show distinct genomic and clinical characteristics compared to their counterparts with abnormal karyotype.

Therapy-related myeloid neoplasms (t-MNs) are a complication of treatment with cytotoxic chemotherapy and/or radiation therapy. The majority of t-MNs show chromosomal abnormalities associated with myelodysplastic syndrome (MDS) or KMT2A rearrangements and are characterized by poor clinical outcomes. A small but substantial subset of patients have normal karyotype (NK) and their clinical characteristics and mutational profiles are not well studied. We retrospectively studied patients diagnosed with t-MN at three institutions and compared the mutational profile and survival data between t-MNs with NK and t-MNs with abnormal karyotype (AK). A total of 204 patients with t-MN were identified including 158 with AK and 46 with NK. NK t-MNs, compared to AK, were enriched for mutations in TET2 (p < 0.0001), NPM1 (p < 0.0001), ASXL1 (p = 0.0003), SRSF2 (p < 0.0001), RUNX1 (p = 0.0336) and STAG2 (p = 0.0099) and showed a significantly lower frequency of TP53 mutations (p < 0.0001). Overall survival (OS) was significantly lower in AK t-MNs as compared to NK cases (p = 0.0094). In our study, NK t-MNs showed a significantly better OS, a higher prevalence of MN-associated mutations and a lower frequency of TP53 mutations compared to their AK counterparts. The distinct clinical and mutational profile of NK t-MNs merits a separate classification.

TRUE-Bolivia: Trauma Responders Unifying to Empower Communities in Santa Cruz, Bolivia.

BACKGROUND: The aim of this study is to assess the efficacy of the TRUE-Bolivia (Trauma Responders Unifying to Empower Communities Bolivia) trauma first responder course at improving participant confidence in first responder abilities and increasing knowledge of trauma response skills. METHODS: Participants attended the 4-h TRUE-Bolivia course at the municipal department of urban transportation and universities and medical schools in Santa Cruz, Bolivia and completed a demographic survey and pre- and post-course knowledge assessments. All participants who attended the full course and completed both knowledge assessments were included in the study, with 453 people attending at least one portion of the course and 329 completing the full course and assessments. RESULTS: A majority of participants were men, had completed high school or attended university, and worked or trained in the fields of transportation or medicine. Participant ratings of confidence on a 5-point Likert scale improved from a median of 3 (interquartile range [IQR] 2) before the course to 5 (IQR 1) after the course (P < 0.01). The median number of correct answers on the pre-course nine-question knowledge assessment was 3 (IQR 3), improving to 7 (IQR 3) on the post-course assessment (P < 0.01). All demographic groups demonstrated improvements in scores from the pre- to post-test. Female gender, higher education level, a background in medicine, and prior training in first aid were associated with higher pre- and post-test scores. CONCLUSIONS: The TRUE-Bolivia course increased knowledge of first responder skills and improved confidence in these abilities in participants from a variety of backgrounds. Further study is needed to determine the long-term skill utilization by participants and the course's impact on local trauma morbidity and mortality.

Direct oral anticoagulants decrease treatment failure for acute lower extremity deep venous thrombosis.

OBJECTIVE: Optimal medical therapy for acute lower extremity deep venous thrombosis (DVT) remains an enigma. While clinical trials demonstrate non-inferiority with an oral anti-Xa inhibitor, or direct oral anticoagulant (DOAC), versus combined low-molecular weight heparin (LMWH) and oral vitamin K antagonist (VKA), the most effective regimen remains to be determined. METHODS: This study is a single-center retrospective cohort study from October 2014 to December 2015 of patients with a diagnosis of acute DVT and subsequent serial lower extremity venous duplex. Demographics, medical history, medications, serial ultrasound findings, as well as the primary anticoagulant used for treatment were collected and analyzed by two independent data extractors. Treatment failure was defined as any new DVT or progression of an existing DVT within 3 months of diagnosis of the index clot. Risk factors for treatment failure were assessed using standard odds ratios and Fischer's exact test. RESULTS: Among 496 patients with an acute lower extremity DVT, 54% (n = 266) were men, mean age was 61 years, 35% (n = 174) involved the popliteal or more proximal segments, and 442 had documentation of the primary treatment for DVT: 20% (n = 90) received nothing; 20% (n = 92) received an oral VKA; 34% (n = 149) received a DOAC; 20% (n = 90) received LMWH; and 5% (n = 21) received another class of anticoagulant. Within 3 months, 21% (n=89 out of 427) had treatment failure defined as any new DVT or progression of prior DVT. Patients treated with a DOAC were less likely to experience treatment failure when compared with any other treatment (odds ratio 0.43; 95% confidence intervals [0.23, 0.79]; p = 0.0069) and when compared with traditional oral VKA (OR 0.44; 95% CI [0.21, 0.92]; p = 0.029). None of prior history of DVT, pulmonary embolism, thrombophilia, renal insufficiency, hepatic insufficiency, cancer, or antiplatelet therapy correlated with treatment failure. Treatment outcome did not correlate with being on any anticoagulation versus none (p = 0.74), nor did it correlate with the duration of treatment (<3 months versus ≥3 months) (p = 0.42). Proximal and distal DVTs showed no difference in treatment failure (19% versus 22%, respectively; p = 0.43). CONCLUSION: In summary, the use of a DOAC for acute lower extremity DVT yielded better overall outcomes and fewer treatment failures at 3 months as compared to traditional oral VKA therapy based on serial duplex imaging.

The Comorbidity-Polypharmacy Score is an Objective and Practical Predictor of Outcomes and Mortality after Vascular Surgery.

BACKGROUND: The comorbidity-polypharmacy score (CPPS) was developed to quantify the severity of comorbidities of patients with geriatric trauma. CPPS is the sum of the number of medications and comorbidities, and is thus objective, user-friendly, and potentially adaptable to many clinical situations. We sought to understand if CPPS associates with outcomes and mortality after common vascular surgery procedures. METHODS: This is a retrospective single-center study. A total of 466 patients who underwent carotid endarterectomy, infrainguinal bypass, percutaneous lower extremity revascularization, or endovascular abdominal aortic aneurysm repair at a single medical center were included. CPPS were classified as mild, moderate, severe, and morbid based on scores of 0-7, 8-15, 15-21, and ≥21, respectively. End points were reinterventions, 30-day readmission, and mortality. We used chi-squared tests to analyze differences in categorical variables; Kruskal-Wallis tests to analyze differences in continuous variables; Kaplan-Meier estimation and Cox proportional hazard modeling to examine survival data; and receiver operator characteristic (ROC) curve analyses to assess sensitivity and specificity. RESULTS: The mean preoperative CPPS was 14.1 ± 6.1. Higher CPPS were associated with longer hospital and postoperative length of stay (P < 0.001). Severe and morbid CPPS categories had higher rates of ICU admission, reintervention, and 30-day readmission which did not reach statistical significance after correction for multiple comparisons. CPPS was independently associated with 1- and 5-year mortality in a multivariable Cox model (hazard ratio = 2.2, 95% confidence interval: 1.3-3.3). ROC analysis revealed C-statistics of 0.81 and 0.72 for 1-year and 5-year all-cause mortality, respectively (P < 0.001). CONCLUSIONS: CPPS is a simple and pragmatic clinical tool for quantifying risk of postoperative outcomes and mortality after common vascular surgery procedures. Further investigation is needed to validate the use of CPPS in enhancing existing predictors of patient outcomes and in serving as an adjunctive tool for determining resource allocation and discharge planning in patients who underwent vascular surgery.

Sarcopenia predicts mortality and adverse outcomes after endovascular aneurysm repair and can be used to risk stratify patients.

BACKGROUND: Endovascular aneurysm repair (EVAR) is currently the most common treatment of abdominal aortic aneurysms. Potential predictors of long-term survival after EVAR include physiologic, functional, and cognitive status, but assessments of these conditions have been difficult to standardize. Objective radiographic findings, such as skeletal muscle atrophy, or sarcopenia, may provide an additional means for selection of patients. This study investigates sarcopenia as a method to predict 1-year survival in patients undergoing EVAR. METHODS: A single-institution retrospective review was conducted of all patients who underwent elective EVAR from September 2002 to June 2014. Patients with an available periprocedural computed tomography (CT) scan and clinical data were included in the analysis. Normalized total psoas cross-sectional area (nTPA) was measured on axial CT images using the area of the bilateral psoas muscle at the third lumbar vertebral level normalized to the square of patient height. A threshold for optimal estimate of sarcopenia based on nTPA was determined using a receiver operating characteristic curve. Sarcopenia was evaluated as an independent risk predictor using univariate, multivariate, and survival analysis. RESULTS: A total of 272 EVAR-treated patients were evaluated, including 237 men and 35 women with a median age of 72 years and mean body mass index of 28.6 kg/m2. There was a significant increase in overall mortality in patients in the lowest quartile of nTPA (Q1, 23.53%; Q2, 13.24%; Q3, 7.35%; Q4, 5.88%; P = .01). The estimated nTPA threshold for increased mortality after EVAR was 500 mm2/m2. Using this threshold, sarcopenia accounted for 57% of the risk effect in our 1-year survival model. CONCLUSIONS: Sarcopenia can assist in identifying EVAR candidates who are less likely to benefit from surgery. It can be readily evaluated from preoperative CT scans and may be a useful tool in evaluation of abdominal aortic aneurysm patients with applications in risk evaluation and telemedicine.

Cost analysis of bronchoalveolar lavage and respiratory tract biopsies in the diagnosis and management of suspected invasive fungal infection in children with cancer or who have undergone stem cell transplant.

BACKGROUND: Identification of an organism is the gold standard for the diagnosis of fungal infection; however, we have previously shown that invasive procedures infrequently lead to a change in management in children with cancer or who have undergone stem cell transplant with suspected respiratory tract invasive fungal infection (RT-IFI). There is also a paucity of data on the cost of RT-IFI in this population. We therefore compared the costs of RT-IFI diagnosed based on CT scan alone versus those who underwent a bronchoalveolar lavage (BAL) or respiratory tract biopsy (RTB). PROCEDURE: We collected cost data on patients at a single center undergoing chemotherapy or who were post-hematopoietic stem cell transplant (HSCT) and were suspected of having RT-IFI between 2007 and 2012. Cost data were included for 14 days from the day of their diagnostic CT scan or procedure. RESULTS: Cost data were available for 76 patients. Thirty-six patients were diagnosed with suspected RT-IFI based on CT only, and 40 patients underwent BAL or RTB. Costs related to chest X-rays (CXRs), inpatient/intensive care unit (ICU) beds, anesthesia, operating room (OR) time, and procedures were significantly higher in the BAL/RTB group versus CT scan group (all P < 0.01). Costs related to CT scans were significantly higher in the CT scan group (P = 0.0002). Overall costs were significantly higher for patients who underwent BAL or RTB versus CT scan only (P < 0.0001). CONCLUSION: Our previous data showed that BAL and RTB infrequently led to a change in management in this population. We now demonstrate that this strategy is costly as well.

A comparative effectiveness analysis of the PBCG vs. PCPT risks calculators in a multi-ethnic cohort.

BACKGROUND: Predictive models that take race into account like the Prostate Cancer Prevention Trial Risk Calculator 2.0 (PCPT RC) and the new Prostate Biopsy Collaborative Group (PBCG) RC have been developed to equitably mitigate the overdiagnosis of prostate specific antigen (PSA) screening. Few studies have compared the performance of both calculators across racial groups. METHODS: From 1485 prospectively recruited participants, 954 men were identified undergoing initial prostate biopsy for abnormal PSA or digital rectal examination in five Chicago hospitals between 2009 and 2014. Discrimination, calibration, and frequency of avoided biopsies were calculated to assess the performance of both risk calculators. RESULTS: Of 954 participants, 463 (48.5%) were Black, 355 (37.2%) were White, and 136 (14.2%) identified as Other. Biopsy results were as follows: 310 (32.5%) exhibited no cancer, 323 (33.9%) indolent prostate cancer, and 321 (33.6%) clinically significant prostate cancer (csPCa). Differences in area under the curve (AUC)s for the detection of csPCa between PCPT and PBCG were not statistically different across all racial groups. PBCG did not improve calibration plots in Blacks and Others, as it showed higher levels of overprediction at most risk thresholds. PCPT led to an increased number of avoidable biopsies in minorities compared to PBCG at the 30% threshold (68% vs. 28% of all patients) with roughly similar rates of missed csPCa (23% vs. 20%). CONCLUSION: Significant improvements were noticed in PBCG's calibrations and net benefits in Whites compared to PCPT. Since PBCG's improvements in Blacks are disputable and potentially biases a greater number of low risk Black and Other men towards unnecessary biopsies, PCPT may lead to better biopsy decisions in racial minority groups. Further comparisons of commonly used risk calculators across racial groups is warranted to minimize excessive biopsies and overdiagnosis in ethnic minorities.

Effect of Nonmyeloablative Hematopoietic Stem Cell Transplantation vs Continued Disease-Modifying Therapy on Disease Progression in Patients With Relapsing-Remitting Multiple Sclerosis: A Randomized Clinical Trial.

Importance: Hematopoietic stem cell transplantation (HSCT) represents a potentially useful approach to slow or prevent progressive disability in relapsing-remitting multiple sclerosis (MS). Objective: To compare the effect of nonmyeloablative HSCT vs disease-modifying therapy (DMT) on disease progression. Design, Setting, and Participants: Between September 20, 2005, and July 7, 2016, a total of 110 patients with relapsing-remitting MS, at least 2 relapses while receiving DMT in the prior year, and an Expanded Disability Status Scale (EDSS; score range, 0-10 [10 = worst neurologic disability]) score of 2.0 to 6.0 were randomized at 4 US, European, and South American centers. Final follow-up occurred in January 2018 and database lock in February 2018. Interventions: Patients were randomized to receive HSCT along with cyclophosphamide (200 mg/kg) and antithymocyte globulin (6 mg/kg) (n = 55) or DMT of higher efficacy or a different class than DMT taken during the previous year (n = 55). Main Outcomes and Measures: The primary end point was disease progression, defined as an EDSS score increase after at least 1 year of 1.0 point or more (minimal clinically important difference, 0.5) on 2 evaluations 6 months apart, with differences in time to progression estimated as hazard ratios. Results: Among 110 randomized patients (73 [66%] women; mean age, 36 [SD, 8.6] years), 103 remained in the trial, with 98 evaluated at 1 year and 23 evaluated yearly for 5 years (median follow-up, 2 years; mean, 2.8 years). Disease progression occurred in 3 patients in the HSCT group and 34 patients in the DMT group. Median time to progression could not be calculated in the HSCT group because of too few events; it was 24 months (interquartile range, 18-48 months) in the DMT group (hazard ratio, 0.07; 95% CI, 0.02-0.24; P < .001). During the first year, mean EDSS scores decreased (improved) from 3.38 to 2.36 in the HSCT group and increased (worsened) from 3.31 to 3.98 in the DMT group (between-group mean difference, -1.7; 95% CI, -2.03 to -1.29; P < .001). There were no deaths and no patients who received HSCT developed nonhematopoietic grade 4 toxicities (such as myocardial infarction, sepsis, or other disabling or potential life-threatening events). Conclusions and Relevance: In this preliminary study of patients with relapsing-remitting MS, nonmyeloablative HSCT, compared with DMT, resulted in prolonged time to disease progression. Further research is needed to replicate these findings and to assess long-term outcomes and safety. Trial Registration: ClinicalTrials.gov Identifier: NCT00273364.

A prospective, randomised controlled trial evaluating the effectiveness of the fluid immersion simulation system vs an air-fluidised bed system in the acute postoperative management of pressure ulcers: A midpoint study analysis.

The use of pressure-offloading support surfaces is considered the standard of care for pressure ulcers (PUs) by most surgeons. The fluid immersion simulation system (FIS) has shown significant results in previous studies. We compared it, for the first time, with a representative air-fluidised bed (AFB) for outcomes related to post-surgical flap closures. This trial was performed over 25 months, in which 40 subjects between 18 and 85 years of age with ≤2 PUs and history of <3 surgical closures underwent reconstruction by one surgeon. Subjects were randomly assigned to either treatment group for 2 weeks after closure. The primary endpoint was success of closure after the study period. Secondary endpoints included incidence of complications and nursing and patient acceptability of the device. The FIS group included 19 subjects, and the AFB group included 21. Flap failure rate was similar between groups (15% vs 17%; P = .99). The Minor complications rate, particularly dehiscence, was higher in the FIS group (66.7% vs 15%; P = .02). Nurse and patient self-reported acceptability had better mean numeric scores in the FIS compared with AFB (nurse: 1.5 vs 1.9; P = .12; patient: 1.9 vs 2.2; P = .14). Further analysis will be conducted to gain better insight on the FIS as an alternative treatment for PUs.

Plasma microbiome-modulated indole- and phenyl-derived metabolites associate with advanced atherosclerosis and postoperative outcomes.

OBJECTIVE: Multiple studies have shown that gut microbes contribute to atherosclerosis, and there is mounting evidence that microbial metabolism of dietary nutrients influences pathophysiology. We hypothesized that indole- and phenyl-derived metabolites that originate solely or in part from bacterial sources would differ between patients with advanced atherosclerosis and age- and sex-matched controls without clinically apparent atherosclerosis. METHODS: Plasma from the advanced atherosclerosis cohort (n = 100) was from patients who underwent carotid endarterectomy, open infrainguinal leg revascularization, or major leg amputation for critical limb ischemia. The controls (n = 22) were age- and sex-matched participants who had no peripheral arterial disease or history of stroke or myocardial infarction. Patients with chronic kidney disease were excluded. Metabolites and internal standards were measured using high-performance liquid chromatography and tandem mass spectrometry. RESULTS: Plasma metabolite concentrations differed significantly between the advanced atherosclerosis and control cohorts. After adjustment for traditional atherosclerosis risk factors, indole (odds ratio [OR], 0.84; 95% confidence interval [CI], 0.75-0.95; P = .004), tryptophan (OR, <0.001; 95% CI, <0.001-0.003; P < .001), indole-3-propionic acid (OR, 0.27; 95% CI, 0.019-0.91; P = .02), and indole-3-aldehyde (OR, 0.12; 95% CI, 0.014-0.92; P = .04) concentrations negatively associated with advanced atherosclerosis, whereas the kynurenine/tryptophan ratio (OR, 61.7; 95% CI, 1.9->999; P = .02) was positively associated. Furthermore, tryptophan and indole-3-propionic acid concentrations (Spearman coefficients of 0.63 and 0.56, respectively; P < .001) correlated with the ankle-brachial index, a surrogate for overall atherosclerotic disease burden. Fourteen patients experienced a major postoperative cardiac complication within 30 days in the advanced atherosclerosis cohort, which was associated with baseline kynurenine/tryptophan ratio (P = .001) and hippuric acid (P = .03). In a multivariate analysis, only the kynurenine/tryptophan ratio remained significantly associated with a postoperative cardiac complication (OR, 44.1; 95% CI, 3.3-587.1; P = .004). Twenty patients in the advanced atherosclerosis cohort experienced a major adverse cardiac event during the follow-up period, which was associated with hippuric acid (P = .002) and the kynurenine/tryptophan ratio (P < .001) at baseline. Both hippuric acid and the kynurenine/tryptophan ratio were independently associated with a major adverse cardiac event in multivariate analyses that included diabetes mellitus. CONCLUSIONS: Specific microbe-derived metabolite signatures associate with advanced human atherosclerosis and postoperative cardiac complications. We suggest that these metabolites are potential novel biomarkers for atherosclerotic disease burden and that further investigation into mechanistic links between defined microbial metabolic pathways and cardiovascular disease is warranted.

Postoperative stereotactic radiosurgery for patients with resected brain metastases: a volumetric analysis.

PURPOSE: Postoperative stereotactic radiosurgery (SRS) is increasingly utilized following resection of brain metastases (BM); however, there are no volumetric data guiding dose selection. We performed a volumetric analysis to guide cavity SRS dosing for resected BM. METHODS: 83 consecutive patients with gross total resection who underwent postoperative SRS to 90 cavities were identified. The 12 Gy isodose lines (V12total) along with the volume of brain parenchyma receiving 12 Gy excluding cavity fluid, ventricular fluid, and calvarium (V12parenchyma) were contoured. Local recurrence (LR) and radionecrosis (RN) were calculated using cumulative incidence rates. Multivariate analysis (MVA) and cutpoint analysis were conducted. RESULTS: Median follow-up was 12.3 months; median dose was 16 Gy. 1- and 2-year cumulative incidence rates of LR were 7.9% and 11.0%. Radiation dose [hazard ratio (HR) 2.04, p = 0.002] was significantly associated with time to LR on MVA. 1- and 2-year cumulative incidence rates of RN were 2.6% and 5.5% respectively. MVA demonstrated increased risk of RN with a larger V12parenchyma (HR 1.46, p = 0.0496). Cavities ≤ 10 cc showed a low 2-year RN risk (4.3%), but had a modest LR risk (13.9%). A radiation dose ≥ 18 Gy significantly improved LC (HR 4.79, p = 0.01). CONCLUSIONS: V12parenchyma should be examined in postoperative SRS to assess RN risk. Cavities > 10 cc treated with 16 Gy achieved excellent LC and minimal RN at 2 years. Cavities ≤ 10 cc may be better treated with a dose ≥ 18 Gy to significantly improve LC given the low RN rate observed with 16 Gy.

Comparison of Direct and Less Invasive Techniques for the Treatment of Severe Aorto-Iliac Occlusive Disease.

BACKGROUND: Severe aorto-iliac occlusive disease (AIOD) is traditionally treated with aorto-bifemoral bypass (ABF) or aorto-unifemoral bypass (AUF). However, cross-femoral bypass (CFB) and hybrid femoral endarterectomy and patch angioplasty with iliac stenting (EPS) have gained popularity as less invasive options. We sought to compare 1-year survival, primary patency, and major amputation rates between open surgical (ABF and AUF) and 2 less invasive reconstruction techniques (CFB and EPS) using a large, multicenter cohort. STUDY DESIGN: This is a retrospective cohort study of patients who underwent either ABF/AUF or CFB/EPS for AIOD between 2006 and 2013 in the Society for Vascular Surgery Vascular Quality Initiative registry. Baseline patient and periprocedural variables were compared. Propensity score matching (PSM) was performed to predict the likelihood of more invasive repair. Kaplan-Meier analysis and Cox models were performed for 1-year survival, primary patency, and major amputation. RESULTS: 1872 patients underwent procedures for AIOD, including 1,133 ABF/AUF and 739 CFB/EPS, during the study period. Indication was critical limb ischemia in 47.3% (n = 886). Median follow-up time was 305 days (range, 10-406). After PSM, the matched cohort included 1,094 ABF/AUF and 711 CFB/EPS patients. Multivariate analysis revealed that patient factors and procedure indication were significant predictors of 1-year mortality and major amputation, but not procedure type. ABF/AUF was associated with improved primary patency over CFB/EPS at 1 year (94.1% ± 1.1% vs. 92.3% ± 1.5%, hazard ratio 0.65, 95% confidence interval 0.45-0.94; P = 0.02). CONCLUSIONS: In a propensity-matched cohort from a multicenter vascular surgery registry, a direct approach to AIOD (ABF/AUF) demonstrated better 1-year primary patency than commonly used less invasive strategies. However, treatment approach was not a predictor of 1-year survival or limb salvage, suggesting that patient factors and procedure indication have a greater impact on outcome.

Impact of Body Mass Index on Outcomes after Mesenteric Revascularization for Chronic Mesenteric Ischemia.

BACKGROUND: Historically, patients with chronic mesenteric ischemia (CMI) are underweight with a low body mass index (BMI). However, with the recent obesity epidemic many of these patients now are overweight with a high BMI. We evaluated the impact of BMI on outcomes after mesenteric revascularization for CMI. METHODS: A retrospective chart review of patients undergoing open or endovascular mesenteric revascularization for CMI between January 2000 and June 2015 was performed. Demographics, comorbidities, BMI, Society for Vascular Surgery-combined comorbidity score, treatment modality, postoperative complications, reintervention, and all-cause mortality were analyzed. The primary end point for the study was all-cause mortality at 5 years. Patients were stratified using the World Health Organization BMI criteria. Univariate, Kaplan-Meier survival, and multivariate analyses were performed. RESULTS: In the study period, 104 unique patients underwent mesenteric revascularization for CMI, for 77 of whom BMI information was available. Of these 77, 30 patients were treated by endovascular revascularization, and 47 patients were treated by open revascularization. Overall, 27 (35.1%) were overweight or obese with a BMI ≥25. Median follow-up time was 41 months. High BMI patients were less likely to have weight loss at the time of surgery (P = 0.004). Stratified by BMI <25 versus BMI ≥25, 5-year survival for patients treated by open revascularization was 90% versus 50% (P = 0.02); survival for patients treated by endovascular revascularization was 27% vs. 53% (P = 0.37). Multivariate survival analysis identified active smoking, hypertensive chronic kidney disease, open repair with the use of venous conduit instead of prosthetic conduit (P < 0.001), and history of peripheral arterial disease (PAD) (P = 0.002), as independent predictors of increased all-cause mortality. CONCLUSIONS: BMI needs to be considered in assessing and counseling patients on outcomes of mesenteric revascularization for CMI, as a BMI over 25 is associated with poorer long-term survival after open revascularization. Smoking, hypertensive chronic kidney disease, PAD, and open repair with the use of venous conduit are independent predictors of long-term mortality after mesenteric revascularization independent of BMI.

Serum adipokine levels and associations with patient-reported fatigue in systemic lupus erythematosus.

Physical activity ameliorates fatigue in systemic lupus erythematosus (SLE) patients by an unknown mechanism. Adipokines, which are influenced by adiposity and physical activity, may be associated with patient-reported fatigue. We describe cross-sectional associations between adipokines and fatigue, physical activity, and SLE disease activity. We measured adipokines, self-reported fatigue, and objective physical activity in 129 SLE patients. Fatigue was assessed with the Fatigue Severity Scale (FSS) and Patient Reported Outcomes Measurement Information System® (PROMIS®) Fatigue score. Disease activity was measured with the Safety of Estrogens in Systemic Lupus Erythematosus National Assessment-Systemic Lupus Erythematosus Disease Activity Index (SELENA-SLEDAI). Participants wore an accelerometer for 7 days to measure physical activity. Leptin, adiponectin, and resistin were measured in stored serum with a Luminex bead-based assay. Multivariable regression models assessed relationships between fatigue and adipokines, and Spearman correlation coefficients summarized associations between adipokines, physical activity, and SELENA-SLEDAI. Median adipokine levels were: leptin 30.5 ng/ml (Interquartile Range 14.0, 56.6), adiponectin 11.6 µg/ml (7.2, 16.8) and resistin 1.4 ng/ml (1.0, 2.2). Associations between adipokines and FSS or PROMIS fatigue were not significant. Body mass index (BMI) ≥ 30 kg/m2 was associated with FSS and PROMIS fatigue in regression analyses (p < 0.05). Weak correlations between leptin, adiponectin, leptin/adiponectin (L/A) ratio, and physical activity and between adiponectin and SELENA-SLEDAI score were not significant after adjusting for BMI. Adipokines were not associated with fatigue in SLE. Adipokines were correlated with physical activity (leptin, adiponectin, L/A ratio) and SLE disease activity (adiponectin), but most of these associations were explained by BMI.

Spectral biomarkers for chemoprevention of colonic neoplasia: a placebo-controlled double-blinded trial with aspirin.

OBJECTIVE: A major impediment to translating chemoprevention to clinical practice has been lack of intermediate biomarkers. We previously reported that rectal interrogation with low-coherence enhanced backscattering spectroscopy (LEBS) detected microarchitectural manifestations of field carcinogenesis. We now wanted to ascertain if reversion of two LEBS markers spectral slope (SPEC) and fractal dimension (FRAC) could serve as a marker for chemopreventive efficacy. DESIGN: We conducted a multicentre, prospective, randomised, double-blind placebo-controlled, clinical trial in subjects with a history of colonic neoplasia who manifested altered SPEC/FRAC in histologically normal colonic mucosa. Subjects (n=79) were randomised to 325 mg aspirin or placebo. The primary endpoint changed in FRAC and SPEC spectral markers after 3 months. Mucosal levels of prostaglandin E2 (PGE2) and UDP-glucuronosyltransferase (UGT)1A6 genotypes were planned secondary endpoints. RESULTS: At 3 months, the aspirin group manifested alterations in SPEC (48.9%, p=0.055) and FRAC (55.4%, p=0.200) with the direction towards non-neoplastic status. As a measure of aspirin's pharmacological efficacy, we assessed changes in rectal PGE2 levels and noted that it correlated with SPEC and FRAC alterations (R=-0.55, p=0.01 and R=0.57, p=0.009, respectively) whereas there was no significant correlation in placebo specimens. While UGT1A6 subgroup analysis did not achieve statistical significance, the changes in SPEC and FRAC to a less neoplastic direction occurred only in the variant consonant with epidemiological evidence of chemoprevention. CONCLUSIONS: We provide the first proof of concept, albeit somewhat underpowered, that spectral markers reversion mirrors antineoplastic efficacy providing a potential modality for titration of agent type/dose to optimise chemopreventive strategies in clinical practice. TRIAL NUMBER: NCT00468910.

A comparison of results of carotid endarterectomy in octogenarians and nonagenarians to younger patients from the Mid-America Vascular Study Group and the Society for Vascular Surgery Vascular Quality Initiative.

OBJECTIVE: Carotid endarterectomy (CEA) reduces stroke risk in selected patients. However, CEA risk profile may be different in older patients. We compared characteristics and outcomes of octogenarians and nonagenarians with those of younger patients. METHODS: Deidentified data from CEA patients were obtained from the Society for Vascular Surgery Vascular Quality Initiative (VQI) database. Prior CEA, carotid artery stent, or combined CEA and coronary artery bypass were excluded, yielding 7390 CEAs in octogenarians and nonagenarians (≥80 years of age) and 35,303 CEAs in younger patients (<80 years of age). We compared post-CEA outcomes, including periprocedural cerebral ischemic events and death, and details such as operative time, bleeding, and return to surgery. RESULTS: Octogenarians and nonagenarians were more likely to have pre-CEA neurologic symptoms (51.4% vs 45.6%; P < .001) and to have never smoked (37.8% vs 22.0%; P < .001), and they were slightly more likely to have required urgent CEA (16.1% vs 13.4%; P < .001). Stenosis ≥70% was similar (octogenarians and nonagenarians, 94.2%; younger patients, 94.4%; P = .45). Perioperative ipsilateral neurologic events and ipsilateral stroke were slightly more common among octogenarians and nonagenarians (1.6% vs 1.1% [P < .001] and 1.2% vs 0.8% [P = .002]). Multivariate modeling (logistic regression) showed that pre-CEA neurologic symptoms (odds ratios, 1.35 [P = .005] and 1.42 [P = .007]), pre-CEA ipsilateral cortical ischemic event (odds ratios, 1.18 [P < .001] and 1.20 [P < .001]), and urgency (odds ratios, 1.75 [P < .001] and 1.67 [P < .001]) remained strong predictors of any ipsilateral neurologic event and any ipsilateral stroke, respectively. However, age ≥80 years remained a significant predictor of these outcomes (odds ratios, 1.37 [P = .003] and 1.44 [P = .004]). Kaplan-Meier estimated survival was lower for octogenarians and nonagenarians at 30 days and 1 year (98.6% vs 99.4% and 93.7% vs 97.0%; log-rank, P < .001). Age ≥80 years was also associated with a greater rate of discharge to other than home after CEA, a difference that was only partially explained by comorbidities in multivariate modeling. CONCLUSIONS: CEA was performed with low rates of perioperative neurologic events and mortality. Multivariate testing showed that the higher rate of neurologic complications in octogenarians and nonagenarians appeared partially related to symptomatic status and urgent surgery; but after adjusting for these factors, age ≥80 years still predicted a slightly higher rate. Periprocedural CEA outcomes appear similar in comparing older and younger patients, although longer term survival is lower for older patients, and older patients are at greater risk of discharge to other than home. CEA was associated with slightly higher risk of neurologic complications in older patients but may be considered appropriate for selected octogenarians and nonagenarians.