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.

Menstrual Phase and Menopausal Status Classification of Benign Breast Tissue Using Hormone-Regulated Gene Expression and Histomorphology: A Validation Study.

BACKGROUND: The validation of breast cancer risk biomarkers in benign breast samples (BBS) is a long-sought goal, hampered by the fluctuation of gene and protein expression with menstrual phase (MP) and menopausal status (MS). Previously, we identified hormone-related gene expression and histomorphology parameters to classify BBS by MS/MP. We now evaluate both together, to validate our prior results. PATIENTS AND METHODS: BBS were obtained from consenting women (86 premenopausal, 55 postmenopausal) undergoing reduction mammoplasty (RM) or contralateral unaffected breast (CUB) mastectomy. MP/MS was defined using classical criteria for menstrual dates and hormone levels on the day of surgery. BBS gene expression was measured with reverse transcription quantitative polymerase chain reaction (RT-qPCR) for three luteal phase (LP) genes (TNFSF11, DIO2, MYBPC1) and four menopausal genes (PGR, GREB1, TIFF1, CCND1). Premenopausal samples were classified into LP or non-LP, using published histomorphology parameters. Logistic regression and receiver-operator curve analysis was performed to assess area under the curve (AUC) for prediction of MP/MS. RESULTS: In all 131 women, menopausal genes plus age > 50 years predicted true MS [AUC 0.93, 95% confidence interval (CI) 0.89, 0.97]. Among premenopausal women, high TNFSF11 expression distinguished non-LP from LP samples (AUC 0.80, 95% CI 0.70, 0.91); the addition of histomorphology improved the prediction nonsignificantly (AUC 0.87, 95% CI 0.78, 0.96). In premenopausal subsets, addition of histomorphology improved LP prediction in RM (AUC 0.95, 95% CI 0.87, 1.0), but not in CUB (0.84, 95% CI 0.72, 0.96). CONCLUSIONS: Expression of five-gene set accurately predicts menopausal status and menstrual phase in BBS, facilitating the development of breast cancer risk biomarkers using large, archived sample repositories.

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.

Implications of Tumor Characteristics and Treatment Modality on Local Recurrence and Functional Outcomes in Children With Chest Wall Sarcoma: A Pediatric Surgical Oncology Research Collaborative Study.

OBJECTIVE: To determine the impact of tumor characteristics and treatment approach on (1) local recurrence, (2) scoliosis development, and (3) patient-reported quality of life in children with sarcoma of the chest wall. SUMMARY OF BACKGROUND DATA: Children with chest wall sarcoma require multimodal therapy including chemotherapy, surgery, and/or radiation. Despite aggressive therapy which places them at risk for functional impairment and scoliosis, these patients are also at significant risk for local recurrence. METHODS: A multi-institutional review of 175 children (median age 13 years) with chest wall sarcoma treated at seventeen Pediatric Surgical Oncology Research Collaborative institutions between 2008 and 2017 was performed. Patient-reported quality of life was assessed prospectively using PROMIS surveys. RESULTS: The most common diagnoses were Ewing sarcoma (67%) and osteosarcoma (9%). Surgical resection was performed in 85% and radiation in 55%. A median of 2 ribs were resected (interquartile range = 1-3), and number of ribs resected did not correlate with margin status ( P = 0.36). Local recurrence occurred in 23% and margin status was the only predictive factor(HR 2.24, P = 0.039). With a median follow-up of 5 years, 13% developed scoliosis (median Cobb angle 26) and 5% required corrective spine surgery. Scoliosis was associated with posteriorrib resection (HR 8.43; P= 0.003) and increased number of ribs resected (HR 1.78; P = 0.02). Overall, patient-reported quality of life is not impaired after chest wall tumor resection. CONCLUSIONS: Local recurrence occurs in one-quarter of children with chest wall sarcoma and is independent of tumor type. Scoliosis occurs in 13% of patients, but patient-reported quality of life is excellent.

The Persistence of Sex Bias in High-Impact Clinical Research.

INTRODUCTION: Sex bias is present in clinical research resulting in disparities in the treatment of women. Our objective was to identify the prevalence of sex inclusiveness of participants in human clinical trials after the passage of National Institutes of Health (NIH) and United States Congress policies in 2015 and 2016 to increase female enrollment in clinical research. METHODS: We performed an observational analysis of data from registered clinical trials published in three high-impact biomedical journals from January 1, 2015 to December 31, 2019. RESULTS: One thousand four hundred and forty two manuscripts with 4,765,783 human subjects were included for analysis. Significantly more males (56%) than females (44%) were included in all three journals (P < 0.0001). Sex matching ≥ 80% was found in 24.6% of publications. Industry funded 43.7% of all studies enrolling significantly more males than females (60.8% versus 39.2%, P < 0.0001). NIH funded 10.2% of studies enrolling significantly more females than males (52.7% versus 47.3%, P < 0.0001). North America and Europe contributed 82.6% of the studies with each enrolling significantly more males than females (P < 0.0001). The United States was the country contributing the most studies (36.1%), enrolling significantly more males than females (55.5% versus 45.5%, P < 0.0001). Cardiovascular disease was the subject area of the most manuscripts among medical specialties (19%), enrolling significantly more males than females (64.9% versus 35.1%, P < 0.0001). Studies analyzed by clinical trial phase, type, trial, and allocation enrolled significantly more males than females (P < 0.0001). CONCLUSIONS: Sex bias remains prevalent in human clinical research trials. Improvements have been made in NIH-funded clinical trials; however, this constitutes a small percentage of overall studies.

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.

Assessing the accuracy of multiparametric MRI to predict clinically significant prostate cancer in biopsy naïve men across racial/ethnic groups.

INTRODUCTION: The Prostate Imaging Reporting and Data System (PIRADS) has shown promise in improving the detection of Gleason grade group (GG) 2-5 prostate cancer (PCa) and reducing the detection of indolent GG1 PCa. However, data on the performance of PIRADS in Black and Hispanic men is sparse. We evaluated the accuracy of PIRADS scores in detecting GG2-5 PCa in White, Black, and Hispanic men. METHODS: We performed a multicenter retrospective review of biopsy-naïve Black (n = 108), White (n = 108), and Hispanic (n = 64) men who underwent prostate biopsy (PB) following multiparametric MRI. Sensitivity and specificity of PIRADS for GG2-5 PCa were calculated. Race-stratified binary logistic regression models for GG2-5 PCa using standard clinical variables and PIRADS were used to calculate area under the receiver operating characteristics curves (AUC). RESULTS: Rates of GG2-5 PCa were statistically similar between Blacks, Whites, and Hispanics (52.8% vs 42.6% vs 37.5% respectively, p = 0.12). Sensitivity was lower in Hispanic men compared to White men (87.5% vs 97.8% respectively, p = 0.01). Specificity was similar in Black versus White men (21.6% vs 27.4%, p = 0.32) and White versus Hispanic men (27.4% vs 17.5%, p = 0.14). The AUCs of the PIRADS added to standard clinical data (age, PSA and suspicious prostate exam) were similar when comparing Black versus White men (0.75 vs 0.73, p = 0.79) and White versus Hispanic men (0.73 vs 0.59, p = 0.11). The AUCs for the Base model and PIRADS model alone were statistically similar when comparing Black versus White men and White versus Hispanic men. CONCLUSIONS: The accuracy of the PIRADS and clinical data for detecting GG2-5 PCa seems statistically similar across race. However, there is concern that PIRADS 2.0 has lower sensitivity in Hispanic men compared to White men. Prospective validation studies are needed.

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.

Phase II study of pazopanib with oral topotecan in patients with metastatic and non-resectable soft tissue and bone sarcomas.

BACKGROUND: Pazopanib is active in refractory soft-tissue sarcoma (STS) and significantly prolongs PFS. Prior studies of combinations of metronomic topotecan with pazopanib have indicated preclinical evidence of response in patients with sarcoma. METHODS: This prospective, single arm, phase II study evaluated the efficacy of the combination of pazopanib with topotecan in patients with metastatic or unresectable non-adipocytic STS. Furthermore, it incorporated exploratory arms for osteosarcoma and liposarcoma. The primary endpoint was progression-free rate at 12 weeks in the non-adipocytic STS cohort. RESULTS: 57.5% of patients in the non-adipocytic STS cohort were progression free at 12 weeks, which did not meet the primary endpoint of the study (66%). The exploratory osteosarcoma cohort exceeded previously established phase II trial comparator data benchmark of 12% with a PFR at 12 weeks of 69.55%. Treatment with the combination of pazopanib and topotecan was accompanied by a grade 3 or 4 toxicities in most patients. CONCLUSIONS: In this prospective trial in refractory metastatic or unresectable STS and osteosarcoma, the combination of pazopanib with topotecan did not meet its primary endpoint of progression-free rate at 12 weeks. The combination of pazopanib with topotecan was associated with a high degree of toxicity.

Long-term outcomes of spinal ependymomas: an institutional experience of more than 60 cases.

PURPOSE: Spinal ependymomas represent the most common primary intramedullary tumors for which optimal management remains undefined. When possible, gross total resection (GTR) is often the mainstay of treatment, with consideration of radiotherapy (RT) in cases of residual or recurrent tumor. The impact of extent of resection and radiotherapy remain understudied. OBJECTIVE: Report on a large institutional cohort with lengthy follow-up to provide information on long-term outcomes and to contribute to limited data assessing the value of extent of resection and RT. METHODS: Patients with pathologically proven primary spinal ependymoma between 1990 and 2018 were identified. Kaplan-Meier estimates were used to calculate progression-free survival (PFS); local-control (LC) and overall survival (OS). Logistic regression was used to analyze variables' association with receipt of RT. RESULTS: We identified 69 patients with ependymoma of which 4 had leptomeningeal dissemination at diagnosis and were excluded. Of the remaining cohort (n = 65), 42 patients (65%) had Grade II spinal ependymoma, 20 (31%) had Grade I myxopapillary ependymoma and 3 (5%) had Grade III anaplastic ependymoma; 54% underwent GTR and 39% underwent RT. With a median follow-up of 5.7 years, GTR was associated with improved PFS. For grade II lesions, STR+RT yielded better outcomes than STR alone (10y PFS 77.1% vs 68.2%, LC 85.7% vs 50%). Degree of resection was the only significant predictor of adjuvant radiotherapy (p < 0.0001). CONCLUSION: Our findings confirm the importance of GTR in spinal ependymomas. Adjuvant RT should be utilized in the setting of a subtotal resection with expectation of improved disease-related outcomes.

The Effect of Obesity on Operating Room Utilization in Breast Surgery.

BACKGROUND: The current obesity epidemic is associated with increased health care costs associated with comorbidities such as diabetes and heart disease as well as postoperative complications. However, the effect of obesity on operating room (OR) utilization, especially in common breast procedures, has not been completely evaluated. Our study is the first to examine the effect of patient obesity on operative time (OPT) for common breast procedures. METHODS: The American College of Surgeons National Surgical Quality Improvement Project databases for 2010-2018 were searched for this retrospective review. Patients undergoing common breast operations (lumpectomy, lumpectomy with sentinel lymph node biopsy (SLNB) (+/- injection), lumpectomy and axillary lymph node dissection (ALND), simple mastectomy, mastectomy with SLNB (+/- injection), and mastectomy with ALND) were filtered out by Current Procedural Terminology code and divided into three groups based on their body mass index (BMI) and weight. Using the two-sample t-test, OPT for the procedures was compared among the lowest and highest BMI and weight categories. We also used a linear regression t-test to demonstrate that for every unit increase in BMI, there was a corresponding increase in OPT for each procedure. RESULTS: When the lowest and highest BMI and weight groups were compared, significant differences in OPT (P < 0.0001) were seen for each of the procedures. Numerous factors that could affect the complexity of surgery and thus OR time were identified. The correlation between BMI and weight and OPT remained significant after controlling for these variables. The differences between the highest and lowest BMI groups were most pronounced for higher complexity procedures, such as lumpectomy with ALND and mastectomy with ALND, with average operating times increasing by 18.2 min and 18.6 min, respectively, for patients with a higher BMI. CONCLUSIONS: Patient BMI and weight significantly affect OPT for common breast procedures. Therefore, patient BMI should be taken into account to improve OR scheduling.

Evaluation of a First Responders Course in Rural North India.

BACKGROUND: Most mortality in trauma occurs in prehospital settings when the golden hour is spent accessing healthcare facilities rather than resuscitating and stabilizing. Assessments performed in the rural community of Nanakpur, India demonstrated a significant paucity of, and limited access to healthcare facilities. To address deficiencies in prehospital care, the All-India Institute of Medical Sciences (AIIMS) constructed the Basic Emergency Care Course (BECC). This study evaluated the BECCs efficacy in Nanakpur. METHODS: The first responder courses took place in 2017 in Nanakpur. Local community health workers, known as Accredited Social Health Activists (ASHAs) were recruited as participants. Participants completed both a pre- and post-course evaluation to assess baseline knowledge and improvement. Participants then took a one-year post-course assessment to evaluate retention. RESULTS: The course included 204 individuals, and over half (109/204) were ASHAs. Pre- and post-course test results were available for 70 participants and demonstrated a significant improvement in knowledge (P < 0.0001). The one-year knowledge retention assessment was completed by 48.6% (n = 53/109) of the original ASHAs. Comparisons between both the pre- and post-course assessment tests with the 12-mo retention assessment revealed a significant decay in knowledge (P < 0.0001). CONCLUSIONS: This study demonstrates the feasibility of utilizing BECC to train ASHAs in Nanakpur as first responders. Participants demonstrated a significant improvement in knowledge immediately after the course. After one year, there was a significant loss in knowledge, highlighting the need for refresher courses. These data suggest potential for the use of BECC for training ASHAs countrywide to strengthen India's prehospital care system.

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.

Predictors and Consequences of Loss to Follow-up after Vascular Surgery.

BACKGROUND: Loss to follow-up (LTF) after surgery impacts quality of care and can adversely affect short- and long-term clinical outcomes. This study identifies modifiable factors contributing to LTF after vascular surgery and the factors' effect on short- and long-term clinical outcomes. METHODS: This is a retrospective single-center cohort study of 440 consecutive adult patients who underwent carotid endarterectomy, infrainguinal bypass, percutaneous lower extremity revascularization, or endovascular aortic aneurysm repair at Northwestern Memorial Hospital between November 2011 and November 2013. Twenty-six patients who died within 9 months after surgery were excluded because of competing risks with the study end points. Demographics, medical history and medications, hospitalization and procedure-related factors, and postoperative complications were collected from the medical record. The primary end point was LTF 1 month after surgery (LTF1M), defined as lack of an in-person outpatient visit with a vascular surgeon 1 month after the index procedure. Secondary outcomes were LTF 1 year after surgery (LTF1Y), defined as lack of an in-person outpatient visit with a vascular surgeon between 9 and 22 months after discharge, and overall 5-year survival. RESULTS: Overall LTF1M and LTF1Y rates were 27.3% and 46.8%, respectively. Kaplan-Meier analysis revealed no difference in survival based on the LTF1M status (P = 0.72), but patients who were LTF1Y had significantly worse survival at 5 years (P < 0.001). Seeing a nonvascular surgeon specialist at our institution (odds ratio (OR) 0.58, 95% confidence interval (CI): 0.35-0.94, P = 0.03) and having a reintervention (OR 0.17, 95% CI: 0.08-0.37, P < 0.001) were associated with decreased LTF1Y in a multivariable model. Overall mortality was more likely with LTF1Y (hazard ratio (HR) 3.27, 95% CI: 1.86-5.76, P < 0.001) and less likely with seeing another specialist at our institution (HR 0.38, 95% CI: 0.20-0.75, P = 0.005). CONCLUSIONS: LTF rates after vascular surgery are high and associated with poor long-term outcomes. Patients who did not see a nonvascular surgeon specialist at our institution had higher rates of LTF1Y and worse overall mortality, suggesting that improved integration of care can improve LTF and survival.

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.

Alvarado Scores Predict Additive Value of Magnetic Resonance Imaging in Workup of Suspected Appendicitis in Children.

BACKGROUND: The presentation of appendicitis in pediatrics is variable, and diagnostic imaging is often used. Magnetic resonance imaging (MRI) is replacing computed tomography in some centers, particularly after a nondiagnostic ultrasound (NDUS). Nonetheless, MRI is not widely used in this setting because of cost, procedure time, institutional capacity, and high rates of negative scans. We hypothesized that the Alvarado Score (AS) could be used to determine the additive diagnostic value of MRI after an NDUS. MATERIALS AND METHODS: Retrospective review of patients aged ≤18 y at a single tertiary care children's hospital who received an ultrasound for suspected appendicitis during 10 consecutive months in 2017. NDUS were defined as nonvisualization of the appendix or secondary signs without radiologic diagnosis. AS were retrospectively calculated from the electronic medical record. Primary outcomes were pathology-confirmed appendicitis, appendectomy, and perforation. RESULTS: AS was determined for 352 patients out of 463 who met inclusion criteria (76%). Sixty-two percent had an NDUS, and 45% of these patients received MRI. Patients with high-risk AS were significantly more likely to have MRI diagnostic of appendicitis (P = 0.0015), and low-risk AS patients were more likely to have a negative or equivocal MRI (P = 0.0169). Twenty-one MRI scans were required per each additional diagnosis of appendicitis in patients with low AS after NDUS versus 4.2 in intermediate-risk AS patients and 2.1 in high-risk AS patients. CONCLUSIONS: Risk stratification with AS can help assess the additive diagnostic utility of MRI after NDUS. MRI may be overutilized for diagnosing acute appendicitis in pediatric patients with low-risk AS.

Impact of Decolonization Protocols and Recurrence in Pediatric MRSA Skin and Soft-Tissue Infections.

BACKGROUND: Methicillin-resistant staphylococcus aureus (MRSA) colonization is associated with the development of skin and soft-tissue infection in children. Although MRSA decolonization protocols are effective in eradicating MRSA colonization, they have not been shown to prevent recurrent MRSA infections. This study analyzed the prescription of decolonization protocols, rates of MRSA abscess recurrence, and factors associated with recurrence. MATERIALS AND METHODS: This study is a single-institution retrospective review of patients ≤18 y of age diagnosed with MRSA culture-positive abscesses who underwent incision and drainage (I&D) at a tertiary-care children's hospital. The prescription of an MRSA decolonization protocol was recorded. The primary outcome was MRSA abscess recurrence. RESULTS: Three hundred ninety-nine patients with MRSA culture-positive abscesses who underwent I&D were identified. Patients with previous history of abscesses, previous MRSA infection groin/genital region abscesses, higher number of family members with a history of abscess/cellulitis or MRSA infection, and I&D by a pediatric surgeon were more likely to be prescribed decolonization. Decolonized patients did not have lower rates of recurrence. Recurrence was more likely to occur in patients with previous abscesses, previous MRSA infection, family history of abscesses, family history of MRSA infection, Hispanic ethnicity, and those with fever on admission. CONCLUSIONS: MRSA decolonization did not decrease the rate of recurrence of MRSA abscesses in our patient cohort. Patients at high risk for MRSA recurrence such as personal or family history of abscess or MRSA infection, Hispanic ethnicity, or fever on admission did not benefit from decolonization.