Erector spinae plane infiltration and anterior rami of spinal nerve: a cadaveric study.

BACKGROUND: The erector spinae plane block (ESP block) is frequently employed for thoracic, abdominal, and spinal surgeries, yet its precise mechanism of action remains a subject of debate. While initially postulated to influence both ventral and dorsal rami of the spinal nerve, recent studies indicate a predominant impact on the dorsal rami with limited involvement of the ventral rami. To elucidate this mechanism, we conducted an observational study to assess the distribution of ESP infiltration to the ventral rami. METHODS: We performed 20 ESP infiltrations bilaterally in 10 unembalmed cadavers, targering the T9 transverse process level. A volume of 20 mL of ropivacaine 0.2% and methylene blue 0.01% was used. Dissection was carried out to assess dye distribution, with a focus on involvement of the ventral and dorsal rami, as well as lateral and longitudinal spread within the spinal muscular plane. RESULTS: No evidence of dye staining was observed in the ventral rami in any of the cadavers; however, the dorsal rami consistently displayed staining. The dye exhibited extensive longitudinal diffusion across the paravertebral musculature, spanning a median of 10 vertebral spaces (T5-L2). The range extended from 3 to 18 spaces, with an IQR of 11 levels (T4-L2), predominantly affecting the longissimus and iliocostalis muscles. CONCLUSIONS: The infiltration of injectate into the ESP does not contact the ventral rami of segmental spinal nerves. The inference that an in vivo ESP block is a paravertebral "by-proxy" is, therefore, unlikely.

Spread of local anesthetic injected in the paravertebral space, intertransverse processes space, and erector spinae plane: a cadaveric model.

INTRODUCTION: Paraspinal fascial plane blocks have become popular and include the erector spinae plane (ESP) and intertransverse process (ITP) blocks. Controversy exists regarding the exact mechanism(s) of these blocks. We aimed to evaluate the spread of local anesthetic (LA) following ESP and ITP blocks as compared with paravertebral (PV) blocks in a cadaveric model. METHOD: Single-injection ultrasound guided ESP (n=5), ITP (n=5), and PV (n=5) blocks were performed in 15 fresh cadaver hemithoraces. The extent of LA spread within the erector spinae fascial plane, involvement of the dorsal ramus, and distribution within the PV space, were qualitatively described. RESULTS: The spread of LA following ESP block extended eight vertebral levels in a cranio-caudal direction, involving the dorsal ramus at each level, but without LA spread into the PV space nor to the ventral rami. LA spread following ITP block extended 1-2 vertebral levels within the PV space and 7 vertebral levels within the erector spinae fascial plane. The spread of LA following PV blocks extended 2-4 vertebral levels, involving the ventral and dorsal ramus at each level, but without LA spread into the ESP. CONCLUSION: Based on the results of this cadaveric experimental model of paraspinal fascial plane blocks, LA spread following ITP blocks extends into both the PV space and the erector spine fascial plane, and thus may offer a more favorable analgesic profile than ESP blocks.

Looking at faces in the wild.

Faces are key to everyday social interactions, but our understanding of social attention is based on experiments that present images of faces on computer screens. Advances in wearable eye-tracking devices now enable studies in unconstrained natural settings but this approach has been limited by manual coding of fixations. Here we introduce an automatic 'dynamic region of interest' approach that registers eye-fixations to bodies and faces seen while a participant moves through the environment. We show that just 14% of fixations are to faces of passersby, contrasting with prior screen-based studies that suggest faces automatically capture visual attention. We also demonstrate the potential for this new tool to help understand differences in individuals' social attention, and the content of their perceptual exposure to other people. Together, this can form the basis of a new paradigm for studying social attention 'in the wild' that opens new avenues for theoretical, applied and clinical research.

Face-Information Sampling in Super-Recognizers.

Perceptual processes underlying individual differences in face-recognition ability remain poorly understood. We compared visual sampling of 37 adult super-recognizers-individuals with superior face-recognition ability-with that of 68 typical adult viewers by measuring gaze position as they learned and recognized unfamiliar faces. In both phases, participants viewed faces through "spotlight" apertures that varied in size, with face information restricted in real time around their point of fixation. We found higher accuracy in super-recognizers at all aperture sizes-showing that their superiority does not rely on global sampling of face information but is also evident when they are forced to adopt piecemeal sampling. Additionally, super-recognizers made more fixations, focused less on eye region, and distributed their gaze more than typical viewers. These differences were most apparent when learning faces and were consistent with trends we observed across the broader ability spectrum, suggesting that they are reflective of factors that vary dimensionally in the broader population.

Partitioning natural face image variability emphasises within-identity over between-identity representation for understanding accurate recognition.

Accurately recognising faces enables social interactions. In recent years it has become clear that people's accuracy differs markedly depending on viewer's familiarity with a face and their individual skill, but the cognitive and neural bases of these accuracy differences are not understood. We examined cognitive representations underlying these accuracy differences by measuring similarity ratings to natural facial image variation. Natural variation was sampled from uncontrolled images on the internet to reflect the appearance of faces as they are encountered in daily life. Using image averaging, and inspired by the computation of Analysis of Variance, we partitioned this variation into differences between faces (between-identity variation) and differences between photos of the same face (within-identity variation). This allowed us to compare modulation of these two sources of variation attributable to: (i) a person's familiarity with a face and, (ii) their face recognition ability. Contrary to prevailing accounts of human face recognition and perceptual learning, we found that modulation of within-identity variation - rather than between-identity variation - was associated with high accuracy. First, familiarity modulated similarity ratings to within-identity variation more than to between-face variation. Second, viewers that are extremely accurate in face recognition - 'super-recognisers' - differed from typical perceivers mostly in their ratings of within-identity variation, compared to between-identity variation. In a final computational analysis, we found evidence that transformations of between- and within-identity variation make separable contributions to perceptual expertise in face recognition. We conclude that inter- and intra-individual accuracy differences primarily arise from differences in the representation of within-identity image variation.

GFMT2: A psychometric measure of face matching ability.

We present an expanded version of a widely used measure of unfamiliar face matching ability, the Glasgow Face Matching Test (GFMT). The GFMT2 is created using the same source database as the original test but makes five key improvements. First, the test items include variation in head angle, pose, expression and subject-to-camera distance, making the new test more difficult and more representative of challenges in everyday face identification tasks. Second, short and long versions of the test each contain two forms that are calibrated to be of equal difficulty, allowing repeat tests to be performed to examine effects of training interventions. Third, the short-form tests contain no repeating face identities, thereby removing any confounding effects of familiarity that may have been present in the original test. Fourth, separate short versions are created to target exceptionally high performing or exceptionally low performing individuals using established psychometric principles. Fifth, all tests are implemented in an executable program, allowing them to be administered automatically. All tests are available free for scientific use via www.gfmt2.org .

Opening injection pressure monitoring using an in-line device does not prevent intraneural injection in an isolated nerve model.

BACKGROUND: Injection pressure monitoring using in-line devices is affordable and easy to implement into a regional anesthesia practice. However, solid evidence regarding their performance is lacking. We aimed to evaluate if opening injection pressure (OIP), measured with a disposable in-line pressure monitor, can prevent intraneural (subepineural) injection using 15 pound per square inch (PSI) as the reference safety threshold. METHODS: An isolated nerve model with six tibial and six common peroneal nerves from three unembalmed fresh cadavers was used for this observational study. A mixture of 0.5% ropivacaine with methylene blue was injected intraneurally at a rate of 10 mL/min, to a maximum of 3 mL. OIP was recorded for each injection as well as evidence of intraneural contrast. Injected volume at 15 and 20 PSI was recorded, and when it leaked out the epineurium, if it occurred. RESULTS: In all cases, OIP was<15 PSI and intraneural contrast was evident before the safety threshold. The 15-20 PSI mark was attained in 5 of 12 injections (41%), with a median injected volume of 0.9 mL (range 0.4-2.3 mL). Peak pressure of >20 PSI was reached in two injections (at 0.6 mL and 2.7 mL). Contrast leaked out the epineurium in 11 of 12 injections (91%) with a median injected volume of 0.6 mL (range 0.1-1.3 mL). CONCLUSIONS: Our results suggest that in-line pressure monitoring may not prevent intraneural injection using an injection pressure of 15 PSI as reference threshold. Due to the preliminary nature of our study, further evidence is needed to demonstrate clinical relevance.

La inteligencia artificial y sus aplicaciones en medicina II: importancia actual y aplicaciones prácticas / Artificial intelligence and its applications in medicine II: Current importance and practical applications

La tecnología y la medicina siguen un camino paralelo durante las últimas décadas. Los avances tecnológicos van modificando el concepto de salud y las necesidades sanitarias están influyendo en el desarrollo de la tecnología. La inteligencia artificial (IA) está formada por una serie de algoritmos lógicos suficientemente entrenados a partir de los cuales las máquinas son capaces de tomar decisiones para casos concretos a partir de normas generales. Esta tecnología tiene aplicaciones en el diagnóstico y seguimiento de pacientes con una evaluación pronóstica individualizada de los mismos. Además, si combinamos esta tecnología con la robótica, podemos crear máquinas inteligentes que hagan propuestas diagnósticas o que sean mucho más eficientes en su trabajo. Por lo tanto la IA va a ser una tecnología presente en nuestro trabajo cotidiano a través de máquinas o programas informáticos, que de manera más o menos transparente para el usuario, van a ir siendo una realidad cotidiana en los procesos sanitarios. Los profesionales sanitarios tenemos que conocer esta tecnología, sus ventajas y sus inconvenientes, porque va a ser una parte integral de nuestro trabajo. En estos dos artículos pretendemos dar una visión básica de esta tecnología adaptada a los médicos con un repaso de su historia y evolución, de sus aplicaciones reales en el momento actual y una visión de un futuro en el que la IA y el Big Data van a conformar la medicina personalizada que caracterizará al siglo XXI

Technology and medicine follow a parallel path during the last decades. Technological advances are changing the concept of health and health needs are influencing the development of technology. Artificial intelligence (AI) is made up of a series of sufficiently trained logical algorithms from which machines are capable of making decisions for specific cases based on general rules. This technology has applications in the diagnosis and follow-up of patients with an individualized prognostic evaluation of them. Furthermore, if we combine this technology with robotics, we can create intelligent machines that make more efficient diagnostic proposals in their work. Therefore, AI is going to be a technology present in our daily work through machines or computer programs, which in a more or less transparent way for the user, will become a daily reality in health processes. Health professionals have to know this technology, its advantages and disadvantages, because it will be an integral part of our work. In these two articles we intend to give a basic vision of this technology adapted to doctors with a review of its history and evolution, its real applications at the present time and a vision of a future in which AI and Big Data will shape the personalized medicine that will characterize the 21st century

[Artificial intelligence and its applications in medicine II: Current importance and practical applications]. / La inteligencia artificial y sus aplicaciones en medicina II: importancia actual y aplicaciones prácticas.

Technology and medicine follow a parallel path during the last decades. Technological advances are changing the concept of health and health needs are influencing the development of technology. Artificial intelligence (AI) is made up of a series of sufficiently trained logical algorithms from which machines are capable of making decisions for specific cases based on general rules. This technology has applications in the diagnosis and follow-up of patients with an individualized prognostic evaluation of them. Furthermore, if we combine this technology with robotics, we can create intelligent machines that make more efficient diagnostic proposals in their work. Therefore, AI is going to be a technology present in our daily work through machines or computer programs, which in a more or less transparent way for the user, will become a daily reality in health processes. Health professionals have to know this technology, its advantages and disadvantages, because it will be an integral part of our work. In these two articles we intend to give a basic vision of this technology adapted to doctors with a review of its history and evolution, its real applications at the present time and a vision of a future in which AI and Big Data will shape the personalized medicine that will characterize the 21st century.

"Triceps Brachii Muscle Response to Neurostimulation of the Radial Nerve during Axillary Plexus Blockade: Clinical, Anatomical and Histological Correlation".

Axillary plexus blockade is a common technique in clinical practice with a well-known pattern of structures around the brachial artery. Historically, the only proper response to radial nerve stimulation was considered to be extension of the hand and wrist. Twenty-five axillary blockades were assessed by ultrasound and neurostimulation; the principal objective was to correlate the needle position over the radial nerve with the anatomical and histological structure of that nerve. During the procedure, the needle was directed in two ways to reach the medial or lateral margin of the nerve: above the brachial artery or beneath it. Once the needle reached the nerve, the current was augmented gradually until a response was elicited. For the cadaveric anatomical study, eight axillae were dissected and histological samples were examined. The response of the triceps brachii muscle differed significantly between the two approaches to the radial nerve (P < 0.001), and the mean intensity of stimulation was significantly lower when the nerve was accessed above the artery (0.44 ± 0.15 mA) than below it (0.57 ± 0.17 mA) (P = 0.015). A triceps brachii motor response occurs at lower current intensity and lower needle-nerve distance when the radial nerve is accessed above the artery and over the latissimus dorsi tendon. These findings were correlated with the topography of the radial nerve in the axillary fossa. Clin. Anat. 33:578-584, 2020. © 2019 Wiley Periodicals, Inc.

Usefulness of high-resolution ultrasound for small nerve blocks: visualization of intercostobrachial and medial brachial cutaneous nerves in the axillary area.

INTRODUCTION: High-resolution ultrasound (HRU) allows one to identify small nerves, but in the clinical setting, intercostobrachial nerve (ICBN) and medial brachial cutaneous nerve (MBCN) are not identified with conventional portable ultrasound (CPU) devices. The aim of this study is to identify both nerves and describe their relation with specific anatomical structures which could be easily identified with the ultrasound devices available in the clinical setting. METHODS: 21 healthy patients were scanned using HRU bilaterally in the axillary area located over the conjoint tendon to find the ICBN and MBCN and describe their anatomic relations. 5 fresh cadavers were used to validate the previous anatomical findings. ICBN and MBCN ultrasound-guided block was performed with 5 mL of methylene blue and iodine contrast, and the distribution was assessed by both CT scan and dissection. RESULTS: ICBN and MBCN were identified in all cases. The average distance of the ICBN branches to the artery was 35±6 mm in men and 27±5 mm in women. Constant identification of the muscle-tendon junction of the latissimus dorsi muscle with respect to the location of the branches of the ICBN nerve was observed. Dissection and CT scan confirmed these findings. CONCLUSION: HRU is a useful tool to identify ICBN and MBCN nerves, and to describe structures which can be easily identified with CPU use in the clinical setting.

Incidência de complicações biológicas em pacientes tabagistas com história de Periodontite / Incidence of biological complications in smokers with a history of Periodontitis

A terapia reabilitadora com implantes de titânio osseointegráveis, em forma de raiz dentária, vem sendo utilizada de maneira segura desde 1965. No entanto, não há um protocolo estabelecido para manutenção bucal desses pacientes, a exemplo da terapia periodontal de suporte (TPS) empregada em pacientes com periodontite. O objetivo desse trabalho foi testar a hipótese de que pacientes tabagistas e em tratamento da periodontite, quando submetidos a um protocolo de TPS bimestral teriam benefícos em relação à incidência de complicações biológicas perimplantares. Pacientes edêntulos parciais, tabagistas e com periodontite receberam terapia periodontal e, em seguida, foram submetidos à inserção cirúrgica de um ou dois implantes dentários. Antes mesmo da fase pós-cirúrgica de TPS, bimestral ou semestral, 71,4 % desses pacientes apresentaram complicações biológicas perimplantares. Um grupo controle não-tabagista e sem periodontite foi incorporado ao estudo original. Análises dos parâmetros clínicos pelo teste de Kruskal-Wallis e quiquadrado de Pearson demonstraram que a carga tabágica está diretamente relacionada com a ocorrência e a gravidade dos acidentes biológicos perimplantares. Conclui-se que pacientes com história de periodontite e consumo diário superior a 20 cigarros apresentam risco aumentado de desenvolver complicações biológicas perimplantares que inclui a perda precoce de implantes. (AU)

Rehabilitation therapy with osseointegrated titanium implants in the form of tooth root has been used safely since 1965. However, there is no established protocol for oral maintenance of these patients, such as periodontal supportive therapy (TPS) employed in patients with periodontitis. The aim of this study was to test the hypothesis that smokers and those undergoing treatment of periodontitis, when submitted to a bimonthly TPS protocol, would have benefits in relation to the incidence of perimplant biological complications. Partial edentulous, smoking and periodontitis patients received periodontal therapy and then underwent surgical insertion of one or two dental implants. Even before the postoperative phase of TPS, bimonthly or semi-annually, 71.4% of these patients had perimplant biological complications. A non-smoking control group with no periodontitis was incorporated into the original study. Analysis of the clinical parameters by the Kruskal-Wallis test and Pearson's chi-square test showed that the smoking load is directly related to the occurrence and severity of perimplantal biological accidents. It is concluded that patients with a history of periodontitis and daily consumption of more than 20 cigarettes are at increased risk of developing perimplant biological complications including early implant loss. (AU)

MRI and the distribution of bone marrow fat in hip osteoarthritis.

PURPOSE: To characterize the distribution of bone marrow fat in hip osteoarthritis (OA) using magnetic resonance imaging (MRI) and to assess its use as a potential biomarker. MATERIALS AND METHODS: In all, 67 subjects (39 female, 28 male) with either total hip replacement (THA) or different severities of radiographic OA, assessed by Kellgren-Lawrence grading (KLG), underwent 3T MRI of the pelvis using the IDEAL sequence to separate fat and water signals. Six regions of interest (ROIs) were identified within the proximal femur. Within each ROI the fractional-fat distribution, represented by pixel intensities, was described by its mean, standard deviation, skewness, kurtosis, and entropy. RESULTS: Hips were graded: 12 as severe symptomatic (THA), 33 had KLG0 or 1, 9 were KLG2, 11 with KLG3, and 2 with KLG4 were analyzed together. The fractional-fat content in the whole proximal femur did not vary with severity in males (mean (SD) 91.2 (6.0)%) but reduced with severity in females from 89.1 (6.7)% (KLG0,1), 91.5 (2.9)% (KLG2), 85.8 (16.7)% (KLG3,4) to 77.5 (11.9)% (THA) (analysis of variance [ANOVA] P = 0.029). These differences were most pronounced in the femoral head, where mean values fell with OA severity in both sexes from 97.9% (2.5%) (KLG0,1) to 73.0% (25.9%) (THA, P < 0.001) with the largest difference at the final stage. The standard deviation and the entropy of the distribution both increased (P < 0.001). CONCLUSION: Descriptors of the fractional fat distribution varied little with the severity of OA until the most severe stage, when changes appeared mainly in the femoral head, and have, therefore, limited value as biomarkers. LEVEL OF EVIDENCE: 2 J. Magn. Reson. Imaging 2017;45:42-50.

Long-term evaluation of the antimicrobial susceptibility and microbial profile of subgingival biofilms in individuals with aggressive periodontitis.

This study evaluates the antimicrobial susceptibility and composition of subgingival biofilms in generalized aggressive periodontitis (GAP) patients treated using mechanical/antimicrobial therapies, including chlorhexidine (CHX), amoxicillin (AMX) and metronidazole (MET). GAP patients allocated to the placebo (C, n = 15) or test group (T, n = 16) received full-mouth disinfection with CHX, scaling and root planning, and systemic AMX (500 mg)/MET (250 mg) or placebos. Subgingival plaque samples were obtained at baseline, 3, 6, 9 and 12 months post-therapy from 3-4 periodontal pockets, and the samples were pooled and cultivated under anaerobic conditions. The minimum inhibitory concentrations (MICs) of AMX, MET and CHX were assessed using the microdilution method. Bacterial species present in the cultivated biofilm were identified by checkerboard DNA-DNA hybridization. At baseline, no differences in the MICs between groups were observed for the 3 antimicrobials. In the T group, significant increases in the MICs of CHX (p < 0.05) and AMX (p < 0.01) were detected during the first 3 months; however, the MIC of MET decreased at 12 months (p < 0.05). For several species, the MICs significantly changed over time in both groups, i.e., Streptococci MICs tended to increase, while for several periodontal pathogens, the MICs diminished. A transitory increase in the MIC of the subgingival biofilm to AMX and CHX was observed in GAP patients treated using enhanced mechanical therapy with topical CHX and systemic AMX/MET. Both protocols presented limited effects on the cultivable subgingival microbiota.

Long-term evaluation of the antimicrobial susceptibility and microbial profile of subgingival biofilms in individuals with aggressive periodontitis

This study evaluates the antimicrobial susceptibility and composition of subgingival biofilms in generalized aggressive periodontitis (GAP) patients treated using mechanical/antimicrobial therapies, including chlorhexidine (CHX), amoxicillin (AMX) and metronidazole (MET). GAP patients allocated to the placebo (C, n = 15) or test group (T, n = 16) received full-mouth disinfection with CHX, scaling and root planning, and systemic AMX (500 mg)/MET (250 mg) or placebos. Subgingival plaque samples were obtained at baseline, 3, 6, 9 and 12 months post-therapy from 3–4 periodontal pockets, and the samples were pooled and cultivated under anaerobic conditions. The minimum inhibitory concentrations (MICs) of AMX, MET and CHX were assessed using the microdilution method. Bacterial species present in the cultivated biofilm were identified by checkerboard DNA-DNA hybridization. At baseline, no differences in the MICs between groups were observed for the 3 antimicrobials. In the T group, significant increases in the MICs of CHX (p < 0.05) and AMX (p < 0.01) were detected during the first 3 months; however, the MIC of MET decreased at 12 months (p < 0.05). For several species, the MICs significantly changed over time in both groups, i.e., Streptococci MICs tended to increase, while for several periodontal pathogens, the MICs diminished. A transitory increase in the MIC of the subgingival biofilm to AMX and CHX was observed in GAP patients treated using enhanced mechanical therapy with topical CHX and systemic AMX/MET. Both protocols presented limited effects on the cultivable subgingival microbiota.

Chemical composition and evaluation of acute toxicological, antimicrobial and modulatory resistance of the extract of Murraya paniculata.

CONTEXT: Murraya paniculata (Linn) JACK (Rutaceae) is used in traditional medicine in the treatment of diabetes, inflammation, and microbial disorders. OBJECTIVE: This study determined the polyphenol composition and antimicrobial and acute toxicological activity of the hydroethanolic extract of M. paniculata leaves (EEMp). MATERIALS AND METHODS: Chemical composition was evaluated by the Folin-Ciocalteu and AlCl3 assays and by HPLC-DAD. Antibacterial and modulatory activity was determined by the microdilution method. Toxicity was assessed with a single dose of EEMp administered orally at doses of 2000 and 5000 mg/kg body weight/day in male and female Swiss mice. RESULTS: Total phenolic content of the EEMp samples varied from 66.5 to 396.8 mg gallic acid equivalent/g of extract and flavonoid content varied from 0.3 to 31.1 mg quercetin equivalent/g of extract. The principal component identified by HPLC-DAD assay was ellagic acid. The results of oral acute toxicity showed no mortality, changes in hematological parameters, or CNS and ANS toxicities in rats. Biochemical analysis showed a significant increase in glucose and glutamic oxaloacetic transaminase activity and reduction in triglycerides and cholesterol for 5000 and 2000 mg/kg doses, respectively, when compared with the control group. Histopathological evaluation showed no significant microscopic changes. EEMp showed essentially no antimicrobial activity, but when aminoglycosides were combined with EEMp their MIC was reduced. CONCLUSIONS: Significant effects were observed in the acute toxicity assay, but they had no clinical relevance. The results suggest that M. paniculata could be used as a source of natural products with antibacterial resistance-modifying activity, with lower toxicity.

Clinical and microbiological effects of systemic antimicrobials combined to an anti-infective mechanical debridement for the management of aggressive periodontitis: a 12-month randomized controlled trial.

AIM: To compare the 1-year clinical and microbiological outcomes of an enhanced anti-infective therapy with versus without systemic antimicrobials in patients with generalized aggressive periodontitis (GAP). METHODS: In this 12-month randomized, double-blinded, placebo-controlled trial, 35 individuals assigned to a control (n = 17) or test group (n = 18) received full-mouth supra and subgingival ultrasonic debridement followed by scaling and root planing with chlorhexidine rinsing, brushing, and irrigation. Subjects received either amoxicillin (AMX, 500 mg) + metronidazole (MET, 250 mg) or placebos, TID for 10 days. Subgingival samples were obtained and analysed for their composition by checkerboard. Data were subjected to non-parametric tests. RESULTS: Both therapeutic protocols resulted in similar significant clinical improvement for most parameters at 1 year (p < 0.01). The AMX + MET group exhibited shallower residual pockets than the placebo (p = 0.05). Most periodontal pathogens decreased, whereas beneficial bacteria increased in counts in both groups over time (p < 0.0012). High levels of some periodontal and other microbial pathogens were associated with disease persistence regardless treatment. CONCLUSIONS: The enhanced anti-infective mechanical therapy is comparable with its combination with systemic AMX+MET for most clinical parameters and for maintaining low levels of periodontal pathogens for up to 1 year after treatment of GAP.

Reverse translation of phase I biomarker findings links the activity of angiotensin-(1-7) to repression of hypoxia inducible factor-1α in vascular sarcomas.

BACKGROUND: In a phase I study of angiotensin-(1-7) [Ang-(1-7)], clinical benefit was associated with reduction in plasma placental growth factor (PlGF) concentrations. The current study examines Ang-(1-7) induced changes in biomarkers according to cancer type and investigates mechanisms of action engaged in vitro. METHODS: Plasma biomarkers were measured prior to Ang-(1-7) administration as well as 1, 2, 3, 4, and 6 hours after treatment. Tests for interaction were performed to determine the impact of cancer type on angiogenic hormone levels. If a positive interaction was detected, treatment-induced biomarker changes for individual cancer types were assessed. To investigate mechanisms of action, in vitro growth assays were performed using a murine endothelioma cell line (EOMA). PCR arrays were performed to identify and statistically validate genes that were altered by Ang-(1-7) treatment in these cells. RESULTS: Tests for interaction controlled for dose cohort and clinical response indicated a significant impact of cancer type on post-treatment VEGF and PlGF levels. Following treatment, PlGF levels decreased over time in patients with sarcoma (P = .007). Treatment of EOMA cells with increasing doses of Ang-(1-7) led to significant growth suppression at doses as low as 100 nM. PCR arrays identified 18 genes that appeared to have altered expression after Ang-(1-7) treatment. Replicate analyses confirmed significant changes in 8 genes including reduction in PlGF (P = .04) and hypoxia inducible factor 1α (HIF-1α) expression (P < .001). CONCLUSIONS: Ang-(1-7) has clinical and pre-clinical activity for vascular sarcomas that is linked to reduced HIF-1α and PlGF expression.