The prognostic value of [ 123 I]-vascular endothelial growth factor ([ 123 I]-VEGF) in glioma

Abstract

Purpose

Recent studies have shown that tumor vascular endothelial cells and various tumor cells overexpress receptors for vascular endothelial growth factor (VEGF). The aim of this study was to investigate the prognostic value of [¹²³I]-VEGF scintigraphy in patients with histologically verified brain tumors.

Methods

23 consecutive patients (9 women and 14 men aged 30–83 years, mean age 56.6 ± 14.4 years) with histopathologically-verified primary brain tumors were included in the study. All patients had undergone [¹²³I]-VEGF scintigraphy. SPECT examinations of brain were performed 30 min and 18 h after injection. Additional [¹¹C]-methionine PET ([¹¹C]-MET PET) was performed in eight of the 23 patients. Both [¹²³I]-VEGF and [¹¹C]-MET PET were evaluated visually and semiquantitatively by tumor-to-normal brain uptake ratio (T/N ratio). Thresholds of the T/N ratio were evaluated by analysis of receiver operating characteristics (ROC). Overall survival (OS) was estimated using the Kaplan-Meier method.

Results

World Health Organization (WHO) grade IV glioma lesions showed [¹²³I]-VEGF uptake 18 h after the injection, whereas other brain tumors of grade II or III showed negative results. There was no significant difference in the tumor size between VEGF positive and VEGF negative tumors. Patients with [¹²³I]-VEGF T/N ratio threshold <1.32 showed significantly longer survival than patients with T/N ratio ≥ 1.32 (2680 days vs 295 days; P < 0.05). In the subgroup of 16 grade IV glioma patients, significant OS differences were found using a T/N ratio of 1.75 as threshold (T/N ratio < 1.75: 720 days; T/N ≥ 1.75: 183 days; P < 0.05). Significant difference (P < 0.05) was also found in [¹¹C]-MET PET T/N ratios between the grade IV glioma (mean T/N ratio: 3.71) and the grade II or III glioma (mean T/N ratio: 1.74).

Conclusion

Our results suggest that [¹²³I]-VEGF scintigraphy may be useful for visualization of tumor angiogenesis. In addition, [¹²³I]-VEGF may provide relevant prognostic information in patients with glioma.

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89 Zr-trastuzumab PET supports clinical decision making in breast cancer patients, when HER2 status cannot be determined by standard work up

Abstract

Background

Up-to-date information on human epidermal growth factor receptor 2 (HER2) status in breast cancer (BC) is important, as expression can vary during the course of the disease, necessitating anti-HER2 therapy adjustments. Repeat biopsies, however, are not always possible. In this feasibility trial we assessed whether ⁸⁹Zr-trastuzumab PET could support diagnostic understanding and aid clinical decision making, when HER2 status could not be determined by standard work up. Additionally, HER2 status on circulating tumour cells (CTCs) was assessed.

Patients and methods

⁸⁹Zr-trastuzumab PET was performed in patients if disease HER2 status remained unclear after standard work up (bone scan, ¹⁸F-FDG PET, CT and if feasible a biopsy). PET result and central pathologic revision of available tumour biopsies were reported to the referring physician. CTC HER2 status prior to PET was evaluated afterwards and therefore not reported. Diagnostic understanding and treatment decision questionnaires were completed by the referring physicians before, directly after and ≥ 3 months after ⁸⁹Zr-trastuzumab PET.

Results

Twenty patients were enrolled: 8 with two primary cancers (HER2-positive and HER2-negative BC or BC and non-BC), 7 with metastases inaccessible for biopsy, 4 with prior HER2-positive and -negative metastases and 1 with primary BC with equivocal HER2 status. ⁸⁹Zr-trastuzumab PET was positive in 12 patients, negative in 7 and equivocal in 1 patient. In 15/20 patients, ⁸⁹Zr-trastuzumab PET supported treatment decision. The scan altered treatment of 8 patients, increased physicians' confidence without affecting treatment in 10, and improved physicians' disease understanding in 18 patients. In 10/20 patients CTCs were detected; 6/10 showed HER2 expression. CTC HER2 status was not correlated to ⁸⁹Zr-trastuzumab PET result or treatment decision.

Conclusion

⁸⁹Zr-trastuzumab PET supports clinical decision making when HER2 status cannot be determined by standard work up. The impact of CTC HER2 status needs to be further explored.

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Evaluating Venous Drainage in Reverse Flow Pedicles: Available Evidence and Mechanisms

J reconstr Microsurg
DOI: 10.1055/s-0038-1667167

Background The anatomy and physiology of venous drainage in the reversed flow vascular pedicle is controversial and there have been few well-designed, controlled studies to effectively evaluate the physiology. We evaluated the available evidence for venous drainage to synthesize the conclusions of these studies, and to identify areas in need of further research. Methods Electronic databases were searched for articles published from January 1, 1950 to November 1, 2017. A total of 316 citations were screened for inclusion. Fifty articles met inclusion criteria and underwent review, yielding 12 articles for final data analysis. Three principal study types were found: human cadaveric (7), animal (3), human clinical (1), and mixed (1). Results We identified two main theories regarding the mechanism of venous drainage in reverse flow flaps. The "avalvular bypass" theory is based on the findings of intact valves of the venae comitantes, and venous outflow through the crossover pattern of the communicating branches and bypass pattern of the collateral branches. Alternatively, the "valvular incompetence" theory implies that pedicle dissection, proximal ligation, and insetting of the flap cause physiologic changes, such as increased venous pressure, denervation, and simultaneous proximal and distal filling, which together result in valvular insufficiency. Conclusions The mechanism by which retrograde venous outflow occurs in reverse flow flaps remains controversial. Nonetheless, a few well-designed studies have contributed to the understanding of venous anatomy and outflow. Most likely, the true mechanism is based on venous outflow that occurs via the "avalvular bypass" route initially and the "valvular incompetence" route later.
[...]

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Long-Term Outcomes after Double Free Flap Reconstruction for Locally Advanced Head and Neck Cancer

J reconstr Microsurg
DOI: 10.1055/s-0038-1667113

Background The use of simultaneous, multiple free flaps has become a reliable reconstructive option in patients with extensive composite defects after resection of locally advanced head and neck cancer. However, some reluctance remains among reconstructive surgeons with concerns regarding flap outcomes and limited patient survival. Therefore, we evaluated complications, long-term patient survival, and patient-reported outcomes following these extensive head and neck reconstructions. Methods All consecutive patients treated with multiple free flaps for reconstruction of extensive composite defects after resection of locally advanced head and neck cancer between 1999 and 2014 were retrospectively reviewed. Patient charts were evaluated for demographics, treatment details, complications, and patient survival. In addition, all patients alive at the start of the study were asked to complete the 10-item Eat Assessment Tool (EAT-10) and the Intelligibility Rating Scale (IRS). Results Eighty-four simultaneous, multiple free flaps were performed in 42 patients. The predominant free flap combination consisted of a fibula with either an anterolateral thigh (n = 22) or a radial forearm flap (n = 14). Complete flap survival was 95%. Nineteen patients were still alive with a mean follow-up of 55 months. Five-year patient survival was 46.3%. Mean EAT-10 score was 8.4 (range: 0–29), with only one patient reporting problematic swallowing. Ninety percent of the patients had moderate to good speech intelligibility with the IRS. Conclusion Multiple, simultaneous free flaps can be performed safely, leading to acceptable long-term patient survival and patient-reported functional outcomes. Our study demonstrates that it is worthwhile to perform these challenging microvascular reconstructions in patients with locally advanced head and neck cancer.
[...]

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Immediate Unilateral Breast Reconstruction using Abdominally Based Flaps: Analysis of 3,310 Cases

J reconstr Microsurg
DOI: 10.1055/s-0038-1667046

Background The abdomen is the most common area from which tissue is harvested for autologous breast reconstruction. We sought to examine national data to determine the differences in total hospital charges, length of stay (LOS), and early postoperative complications following pedicled transverse rectus abdominis myocutaneous flap (pTRAM), free TRAM (fTRAM), deep-inferior epigastric perforator (DIEP), and superficial inferior epigastric artery perforator (SIEA) flaps. Methods The 2009–2013 Nationwide Inpatient Sample Database was used to identify patients who underwent a unilateral mastectomy and only one type of abdominally based autologous flap (pTRAM, fTRAM, DIEP, and SIEA) during the same hospital admission. Outcomes of interest included total charges, LOS, and complications including revision of vascular anastomosis and hematoma. Results A total of 3,310 cases were identified, corresponding to 15,991 abdominally based unilateral immediate breast reconstructions after standard weighting was applied; 5,079 (31.8%) were pTRAM flaps, 4,461 (27.9%) were fTRAM flaps, 6,206 (38.8%) were DIEP flaps, and 245 (1.5%) were SIEA flaps. The mean total charges for pTRAM, fTRAM, DIEP, and SIEA flaps were $17,765.5, $22,637.6, $25,814.6, and $26,605.2, respectively (p < 0.0001). The mean LOS for pTRAM, fTRAM, DIEP, and SIEA flaps were 96.5, 106.5, 106.7, and 108.9 hours, respectively (p = 0.002). The rates for return to the OR for the revision of a vascular anastomosis for pTRAM, fTRAM, DIEP, and SIEA were 0.0%, 1.72%, 2.66%, and 5.64%, respectively (p < 0.0001). Conclusions There is variation in the total charges, LOS, and early complications between pTRAM, fTRAM, DIEP, and SIEA flap-based breast reconstruction. fTRAM, DIEP, and SIEA flaps incur higher hospital total charges, have longer lengths of stay, and experience more immediate complications compared with pTRAM. Well-designed prospective trials are required to better understand the findings from this study with the inclusion of other critical outcomes such as patient satisfaction, aesthetic results, and long-term outcomes such as abdominal wall morbidity.
[...]

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Postoperative Management of Lower Extremity Free Tissue Transfer: A Systematic Review

J reconstr Microsurg
DOI: 10.1055/s-0038-1667049

Background Free tissue transfer for lower extremity reconstruction is a safe and reliable option for a wide range of challenging wounds; however, no consensus exists regarding postoperative management. Methods A systematic review of postoperative management of lower extremity free tissue transfer was conducted using Medline, Cochrane Database, and Web of Science. Multicenter surveys, randomized controlled trials, cohort studies, and case series were reviewed. Results Fifteen articles investigating current protocols, flap physiology, and aggressive dangle protocols were reviewed. The following evidence-based conclusions were made: (1) Free tissue transfer to the lower extremity is unique due to altered hemodynamics and dependency during orthostasis. Free flap circulation is dependent on locally mediated responses and deprived of compensatory muscular and neurovascular mechanisms that prevent venous congestion in the normal extremity. (2) Compressive wrapping reduces venous congestion and edema and may induce ischemic conditioning, which can increase blood flow. (3) Dangle protocols vary widely in timing of initiation, frequency, and monitoring. Small volume studies examining aggressive mobilization protocols initiating early dependency have led to earlier ambulation and discharge, with no change in flap survival as compared with conservative protocols. (4) Weight bearing may begin after the completion of dangle protocol if no orthopedic injury is present. Conclusions Early initiation of a dangle protocol does not appear to negatively impact flap survival based on this systematic review. Compressive wrapping may be a useful adjunct. Many surgeons agree that clinical monitoring is sufficient; there is no consensus on the utility of adjunct monitoring techniques. Weight bearing may begin after completion of dangle protocol with close flap monitoring, if not prevented by orthopedic restrictions. By providing additional outflow vasculature to reduce venous congestion, flow-through anastomoses may eliminate the need for a dangle protocol. Further research, including large randomized controlled trials is still needed to establish high-level evidence-based conclusions.
[...]

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The 9th Congress of the World Society for Reconstructive Microsurgery

J reconstr Microsurg
DOI: 10.1055/s-0038-1667117

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Perceptual facilitation of word recognition through motor activation during sentence comprehension

Publication date: Available online 29 July 2018

Source: Cortex

Author(s): Nicola Molinaro, Irene F. Monsalve

Abstract

Despite the growing literature on anticipatory language processing, the brain dynamics of this high-level predictive process are still unclear. In the present MEG study, we analyzed pre- and post-stimulus oscillatory activity time-locked to the reading of a target word. We experimentally contrasted the processing of the same target word following two highly constraining sentence contexts, in which the constraint was driven either by the semantic content or by the lexical association between words. Previous research suggests the presence of sensory facilitation for expected words in the latter condition but not in the former. We observed a dissociation between beta (∼20 Hz) and gamma (>50 Hz) band activity in pre- and post-stimulus time intervals respectively. Both the beta and gamma effects were evident in occipital brain regions, and only the pre-stimulus beta effect additionally involved left pre-articulatory motor regions. Lexically constrained (vs. semantically constrained) words elicited reduced beta power around 400 msec before the target word in motor regions and a functionally related gamma enhancement in occipital regions around 200 msec post-target. The present findings highlight the role of the motor network in word-form prediction and support proposals claiming that low-level perceptual representations can be pre-activated during language prediction.

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Contribution of ancient human remains analysis to the understanding of the variability in HLA-B gene variants in relation to the diagnosis of spondyloarthropathies

Publication date: Available online 29 July 2018

Source: Journal of Autoimmunity

Author(s): Imanol M. Laza, Nerea G. Ventades, Montserrat Hervella, Concepción de-la-Rúa

Abstract

Genetic investigations on ancient human remains affected by rheumatological pathologies are a research field of particular interest for identifying the pathogenesis of diseases, especially those having an autoimmune background such as spondyloarthopaties (SpA). Reliable studies concerning this topic require collaboration between multiple disciplines, usually starting from paleopathologic observations up to molecular genetic screening. Here, we focused our investigation in a medieval necropolis in the Basque Country (13th-15th century, N = 163), which presents a high frequency of joint pathologies through two approaches: on the one hand, the analysis of joint manifestations for the differential diagnosis of the SpA and, on the other hand, the determination of the alleles of the HLA-B gene. The morphological analysis allowed determining that 30% of the individuals had rheumatic bone manifestations, with SpA being the most frequent (45%). The genetic analysis of individuals with and without pathologies, based on the study of the HLA-B gene, allowed finding 17 alleles for this gene, with HLA-B40, HLA-B27 and HLA-B35 being the most frequent. Although these alleles have been traditionally described as genetic markers associated to the development of SpA, in this study they were also found in individuals with other rheumatic diseases (osteoarthritis and rheumatoid arthritis) and even in individuals without pathologies. These data confirm the complexity of the relationship of the HLA-B gene variants with SpA, since it is not possible to establish a diagnosis of SpA with these variants alone. However, we suggest that allele HLA-B40, in combination with some specific rheumatic bone manifestations, facilitates the diagnosis of SpA.

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Antibodies targeting circulating protective molecules in lupus nephritis: Interest as serological biomarkers

Publication date: Available online 29 July 2018

Source: Autoimmunity Reviews

Author(s): Chantal Dumestre-Pérard, Giovanna Clavarino, Sophie Colliard, Jean-Yves Cesbron, Nicole M. Thielens

Abstract

Lupus nephritis (LN) is one of the most frequent and severe manifestations of systemic lupus erythematosus (SLE), considered as the major predictor of poor prognosis. An early diagnosis of LN is a real challenge in the management of SLE and has an important implication in guiding treatments. In clinical practice, conventional parameters still lack sensitivity and specificity for detecting ongoing disease activity in lupus kidneys and early relapse of nephritis. LN is characterized by glomerular kidney injury, essentially due to deposition of immune complexes involving autoantibodies against cellular components and circulating proteins. One of the possible mechanisms of induction of autoantibodies in SLE is a defect in apoptotic cells clearance and subsequent release of intracellular autoantigens. Autoantibodies against soluble protective molecules involved in the uptake of dying cells, including complement proteins and pentraxins, have been described. In this review, we present the main autoantibodies found in LN, with a focus on the antibodies against these protective molecules. We also discuss their pathogenic role and conclude with their potential interest as serological biomarkers in LN.

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NF-κB inducing kinase (NIK) is an essential post-transcriptional regulator of T-cell activation affecting F-actin dynamics and TCR signaling

Publication date: Available online 29 July 2018

Source: Journal of Autoimmunity

Author(s): Sonja M. Lacher, Christoph Thurm, Ute Distler, Alma N. Mohebiany, Nicole Israel, Maja Kitic, Anna Ebering, Yilang Tang, Matthias Klein, Guido H. Wabnitz, Florian Wanke, Yvonne Samstag, Tobias Bopp, Florian C. Kurschus, Luca Simeoni, Stefan Tenzer, Ari Waisman

Abstract

NF-κB inducing kinase (NIK) is the key protein of the non-canonical NF-κB pathway and is important for the development of lymph nodes and other secondary immune organs. We elucidated the specific role of NIK in T cells using T-cell specific NIK-deficient (NIK^ΔT) mice. Despite showing normal development of lymphoid organs, NIK^ΔT mice were resistant to induction of CNS autoimmunity. T cells from NIK^ΔT mice were deficient in late priming, failed to up-regulate T-bet and to transmigrate into the CNS. Proteomic analysis of activated NIK^−/- T cells showed de-regulated expression of proteins involved in the formation of the immunological synapse: in particular, proteins involved in cytoskeleton dynamics. In line with this we found that NIK-deficient T cells were hampered in phosphorylation of Zap70, LAT, AKT, ERK1/2 and PLCγ upon TCR engagement. Hence, our data disclose a hitherto unknown function of NIK in T-cell priming and differentiation.

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