Tej D. Azad

Estimate of the global volume of surgery in 2012: an assessment supporting improved health outcomes.

BACKGROUND It was previously estimated that 234·2 million operations were performed worldwide in 2004. The association between surgical rates and population health outcomes is not clear. We re-estimated global surgical volume to track changes over time and assess rates associated with healthy populations. METHODS We gathered demographic, health, and economic data for 194 WHO member states. Surgical volumes were obtained from published studies and other reports from 2005 onwards. We estimated rates of surgery for all countries without available data based on health expenditure in 2012 and assessed the proportion of surgery comprised by caesarean delivery. The rate of surgery was plotted against life expectancy to describe the association between surgical care and this health indicator. FINDINGS We identified 66 countries reporting surgical data between 2005 and 2013. We estimate that 312·9 million operations (95% CI 266·2-359·5) took place in 2012-a 33·6% increase over 8 years; the largest proportional increase occurred in countries spending US

Magnetic resonance image features identify glioblastoma phenotypic subtypes with distinct molecular pathway activities

400 or less per capita on health care. Caesarean delivery comprised 29·8% (5·8 million operations) of the total surgical volume in poor health expenditure countries compared with 10·8% (7·8 million operations) in low health expenditure countries and 2·7% (5·1 million operations) in high health expenditure countries. We noted a correlation between increased life expectancy and increased surgical rates up to 1533 operations per 100 000 people, with significant but less dramatic improvement above this rate. INTERPRETATION Surgical volume is large and continues to grow in all economic environments. A single procedure-caesarean delivery-comprised almost a third of surgical volume in the most resource-limited settings. Surgical care is an essential part of health care and is associated with increased life expectancy, yet many low-income countries fail to achieve basic levels of service. Improvements in capacity and delivery of surgical services must be a major component of health system strengthening. FUNDING None.

Endothelial nitric oxide synthase mediates endogenous protection against subarachnoid hemorrhage-induced cerebral vasospasm.

Quantitative imaging stratifies glioblastoma into three different phenotypes with distinct molecular activities independent of established molecular markers and clinical status. Brain images create cancer clusters When directing therapies toward tumors, a sample of the cancerous tissue is needed to identify molecular targets. For patients with glioblastoma, however, it is invasive to biopsy the brain. Itakura et al. sought to identify noninvasive determinants of tumor phenotype that would potentially correlate with molecular pathways, thus allowing for targeted therapy without such brain invasion. The authors used magnetic resonance imaging to look at solitary, unilateral tumors from 121 glioblastoma patients and then generated nearly 400 unique image features that could be used to describe each tumor. The tumors could be grouped into three different phenotypes or “clusters”: pre-multifocal cluster, with highly irregular tumor shapes; spherical cluster, with defined edges; and rim-enhancing cluster, with a hypointense center ringed by hyperintensity. The distinct clusters were further validated in a separate cohort of 144 patients. These clusters could be used to stratify patients not only according to molecular pathways for targeted therapy but also by survival, indicating the potential for such noninvasive image-based quantitative biomarkers to be used for patient prognosis. Glioblastoma (GBM) is the most common and highly lethal primary malignant brain tumor in adults. There is a dire need for easily accessible, noninvasive biomarkers that can delineate underlying molecular activities and predict response to therapy. To this end, we sought to identify subtypes of GBM, differentiated solely by quantitative magnetic resonance (MR) imaging features, that could be used for better management of GBM patients. Quantitative image features capturing the shape, texture, and edge sharpness of each lesion were extracted from MR images of 121 single-institution patients with de novo, solitary, unilateral GBM. Three distinct phenotypic “clusters” emerged in the development cohort using consensus clustering with 10,000 iterations on these image features. These three clusters—pre-multifocal, spherical, and rim-enhancing, names reflecting their image features—were validated in an independent cohort consisting of 144 multi-institution patients with similar tumor characteristics from The Cancer Genome Atlas (TCGA). Each cluster mapped to a unique set of molecular signaling pathways using pathway activity estimates derived from the analysis of TCGA tumor copy number and gene expression data with the PARADIGM (Pathway Recognition Algorithm Using Data Integration on Genomic Models) algorithm. Distinct pathways, such as c-Kit and FOXA, were enriched in each cluster, indicating differential molecular activities as determined by the image features. Each cluster also demonstrated differential probabilities of survival, indicating prognostic importance. Our imaging method offers a noninvasive approach to stratify GBM patients and also provides unique sets of molecular signatures to inform targeted therapy and personalized treatment of GBM.

Size and distribution of the global volume of surgery in 2012

Background and Purpose— Vasospasm-induced delayed cerebral ischemia remains a major source of morbidity in patients with aneurysmal subarachnoid hemorrhage (SAH). We hypothesized that activating innate neurovascular protective mechanisms by preconditioning (PC) may represent a novel therapeutic approach against SAH-induced vasospasm and neurological deficits and, secondarily, that the neurovascular protection it provides is mediated by endothelial nitric oxide synthase (eNOS). Methods— Wild-type mice were subjected to hypoxic PC or normoxia followed 24 hours later by SAH. Neurological function was analyzed daily; vasospasm was assessed on post-surgery Day 2. Nitric oxide availability, eNOS expression, and eNOS activity were also assessed. In a separate experiment, wild-type and eNOS-null mice were subjected to hypoxic PC or normoxia followed by SAH and assessed for vasospasm and neurological deficits. Results— PC nearly completely prevented SAH-induced vasospasm and neurological deficits. It also prevented SAH-induced reduction in nitric oxide availability and increased eNOS activity in mice with and without SAH. PC-induced protection against vasospasm and neurological deficits was lost in wild-type mice treated with the nitric oxide synthase inhibitor NG-nitro-l-arginine methyl ester and in eNOS-null mice. Conclusions— Endogenous protective mechanisms against vasospasm exist, are powerful, and can be induced by PC. eNOS-derived nitric oxide is a critical mediator of PC-induced neurovascular protection. These data provide strong “proof-of-principle” evidence that PC represents a promising new strategy to reduce vasospasm and delayed cerebral ischemia after SAH.

Early detection of molecular residual disease in localized lung cancer by circulating tumor DNA profiling

Abstract Objective To estimate global surgical volume in 2012 and compare it with estimates from 2004. Methods For the 194 Member States of the World Health Organization, we searched PubMed for studies and contacted key informants for reports on surgical volumes between 2005 and 2012. We obtained data on population and total health expenditure per capita for 2012 and categorized Member States as very-low, low, middle and high expenditure. Data on caesarean delivery were obtained from validated statistical reports. For Member States without recorded surgical data, we estimated volumes by multiple imputation using data on total health expenditure. We estimated caesarean deliveries as a proportion of all surgery. Findings We identified 66 Member States reporting surgical data. We estimated that 312.9 million operations (95% confidence interval, CI: 266.2–359.5) took place in 2012, an increase from the 2004 estimate of 226.4 million operations. Only 6.3% (95% CI: 1.7–22.9) and 23.1% (95% CI: 14.8–36.7) of operations took place in very-low- and low-expenditure Member States representing 36.8% (2573 million people) and 34.2% (2393 million people) of the global population of 7001 million people, respectively. Caesarean deliveries comprised 29.6% (5.8/19.6 million operations; 95% CI: 9.7–91.7) of the total surgical volume in very-low-expenditure Member States, but only 2.7% (5.1/187.0 million operations; 95% CI: 2.2–3.4) in high-expenditure Member States. Conclusion Surgical volume is large and growing, with caesarean delivery comprising nearly a third of operations in most resource-poor settings. Nonetheless, there remains disparity in the provision of surgical services globally.

Therapeutic strategies to improve drug delivery across the blood-brain barrier.

Identifying molecular residual disease (MRD) after treatment of localized lung cancer could facilitate early intervention and personalization of adjuvant therapies. Here, we apply cancer personalized profiling by deep sequencing (CAPP-seq) circulating tumor DNA (ctDNA) analysis to 255 samples from 40 patients treated with curative intent for stage I-III lung cancer and 54 healthy adults. In 94% of evaluable patients experiencing recurrence, ctDNA was detectable in the first posttreatment blood sample, indicating reliable identification of MRD. Posttreatment ctDNA detection preceded radiographic progression in 72% of patients by a median of 5.2 months, and 53% of patients harbored ctDNA mutation profiles associated with favorable responses to tyrosine kinase inhibitors or immune checkpoint blockade. Collectively, these results indicate that ctDNA MRD in patients with lung cancer can be accurately detected using CAPP-seq and may allow personalized adjuvant treatment while disease burden is lowest.Significance: This study shows that ctDNA analysis can robustly identify posttreatment MRD in patients with localized lung cancer, identifying residual/recurrent disease earlier than standard-of-care radiologic imaging, and thus could facilitate personalized adjuvant treatment at early time points when disease burden is lowest. Cancer Discov; 7(12); 1394-403. ©2017 AACR.See related commentary by Comino-Mendez and Turner, p. 1368This article is highlighted in the In This Issue feature, p. 1355.

Anti-CD47 Treatment Stimulates Phagocytosis of Glioblastoma by M1 and M2 Polarized Macrophages and Promotes M1 Polarized Macrophages In Vivo

Resection of brain tumors is followed by chemotherapy and radiation to ablate remaining malignant cell populations. Targeting these populations stands to reduce tumor recurrence and offer the promise of more complete therapy. Thus, improving access to the tumor, while leaving normal brain tissue unscathed, is a critical pursuit. A central challenge in this endeavor lies in the limited delivery of therapeutics to the tumor itself. The blood-brain barrier (BBB) is responsible for much of this difficulty but also provides an essential separation from systemic circulation. Due to the BBBs physical and chemical constraints, many current therapies, from cytotoxic drugs to antibody-based proteins, cannot gain access to the tumor. This review describes the characteristics of the BBB and associated changes wrought by the presence of a tumor. Current strategies for enhancing the delivery of therapies across the BBB to the tumor will be discussed, with a distinction made between strategies that seek to disrupt the BBB and those that aim to circumvent it.

Anterior Versus Posterior Approach for Multilevel Degenerative Cervical Disease: A Retrospective Propensity Score-Matched Study of the MarketScan Database.

Tumor-associated macrophages (TAMs) represent an important cellular subset within the glioblastoma (WHO grade IV) microenvironment and are a potential therapeutic target. TAMs display a continuum of different polarization states between antitumorigenic M1 and protumorigenic M2 phenotypes, with a lower M1/M2 ratio correlating with worse prognosis. Here, we investigated the effect of macrophage polarization on anti-CD47 antibody-mediated phagocytosis of human glioblastoma cells in vitro, as well as the effect of anti-CD47 on the distribution of M1 versus M2 macrophages within human glioblastoma cells grown in mouse xenografts. Bone marrow-derived mouse macrophages and peripheral blood-derived human macrophages were polarized in vitro toward M1 or M2 phenotypes and verified by flow cytometry. Primary human glioblastoma cell lines were offered as targets to mouse and human M1 or M2 polarized macrophages in vitro. The addition of an anti-CD47 monoclonal antibody led to enhanced tumor-cell phagocytosis by mouse and human M1 and M2 macrophages. In both cases, the anti-CD47-induced phagocytosis by M1 was more prominent than that for M2. Dissected tumors from human glioblastoma xenografted within NOD.Cg-Prkdcscid Il2rgtm1Wjl/SzJ mice and treated with anti-CD47 showed a significant increase of M1 macrophages within the tumor. These data show that anti-CD47 treatment leads to enhanced tumor cell phagocytosis by both M1 and M2 macrophage subtypes with a higher phagocytosis rate by M1 macrophages. Furthermore, these data demonstrate that anti-CD47 treatment alone can shift the phenotype of macrophages toward the M1 subtype in vivo.

Improved capture of adverse events after spinal surgery procedures with a longitudinal administrative database

Study Design. Retrospective 2:1 propensity score-matched analysis on a national longitudinal database between 2006 and 2010. Objective. To compare rates of adverse events, revisions procedure rates, and payment differences in anterior cervical fusion procedures compared with posterior laminectomy and fusion procedures with at least 3 levels of instrumentation. Summary of Background Data. The comparative benefits of anterior versus posterior approach to multilevel degenerative cervical disease remain controversial. Recent systematic reviews have reached conflicting conclusions. We demonstrate the comparative economic and clinical outcomes of anterior and posterior approaches for multilevel cervical degenerative disk disease. Methods. We identified 13,662 patients in a national billing claims database who underwent anterior or posterior cervical fusion procedures with 3 or more levels of instrumentation. Cohorts were balanced using 2:1 propensity score matching and outcomes were compared using bivariate analysis. Results. With the exception of dysphagia (6.4% in anterior and 1.4% in posterior), overall 30-day complication rates were lower in the anterior approach group. The rate of any complication excluding dysphagia with anterior approaches was 12.3%, significantly lower (P < 0.0001) than that of posterior approaches, 17.8%. Anterior approaches resulted in lower hospital (

Predicting complication risk in spine surgery: a prospective analysis of a novel risk assessment tool

18,346 vs.