Association between investigator-measured body-mass index and colorectal adenoma: a systematic review and meta-analysis of 168,201 subjects

Abstract

The objective of this meta-analysis is to evaluate the odds of colorectal adenoma (CRA) in colorectal cancer screening participants with different body mass index (BMI) levels, and examine if this association was different according to gender and ethnicity. The EMBASE and MEDLINE were searched to enroll high quality observational studies that examined the association between investigator-measured BMI and colonoscopy-diagnosed CRA. Data were independently extracted by two reviewers. A random-effects meta-analysis was conducted to estimate the summary odds ratio (SOR) for the association between BMI and CRA. The Cochran's Q statistic and I² analyses were used to assess the heterogeneity. A total of 17 studies (168,201 subjects) were included. When compared with subjects having BMI < 25, individuals with BMI 25–30 had significantly higher risk of CRA (SOR 1.44, 95% CI 1.30–1.61; I² = 43.0%). Subjects with BMI ≥ 30 had similarly higher risk of CRA (SOR 1.42, 95% CI 1.24–1.63; I² = 18.5%). The heterogeneity was mild to moderate among studies. The associations were significantly higher than estimates by previous meta-analyses. There was no publication bias detected (Egger's regression test, p = 0.584). Subgroup analysis showed that the magnitude of association was significantly higher in female than male subjects (SOR 1.43, 95% CI 1.30–1.58 vs. SOR 1.16, 95% CI 1.07–1.24; different among different ethnic groups (SOR 1.72, 1.44 and 0.88 in White, Asians and Africans, respectively) being insignificant in Africans; and no difference exists among different study designs. In summary, the risk conferred by BMI for CRA was significantly higher than that reported previously. These findings bear implications in CRA risk estimation.

http://ift.tt/2lh5sQn

Progressive delayed hemidystonia following clinically mild traumatic brain injury

A 16-year-old boy presented with progressive left hemidystonia over 3 years. The possibilities of symptomatic hemidystonia due to focal lesions such as infarct (vasculitis), tumours, tuberculoma, arteriovenous malformations or heredodegenerative disorders such as Wilson disease were considered. Imaging showed a peculiar scar involving right basifrontal region extending upto anterior, centromedian and dorsomedial nuclei of thalamus due to blowout fracture of roof of orbit. This scar was responsible for progressive left hemidystonia. On probing the history, it was revealed that patient had sustained a mild traumatic brain injury (mTBI) 3 years ago. Burke-Fahn-Marsden dystonia severity rating scale showed improvement from 19 to 6 after treatment with tablet trihexyphenidyl 16 mg and clonazepam 1 mg. A linear scar reaching upto thalamus due to blowout fracture of roof of orbit following clinically mTBI is unique. Delayed, progressive hemidystonia has been reported following severe head injury, however is less common following clinically mTBI.

http://ift.tt/2EauTuS

Endobronchial metastasis of mixed Mullerian tumour of the uterus

Endobronchial metastasis occurs in only 2%–5% of non-pulmonary cancers. Here we report on an 84-year-old woman who presented with breathlessness and light-headedness while on holiday in Australia, 2 years post-treatment for endometrial cancer. Initial CT pulmonary angiogram identified a soft tissue mass in the left hemithorax. A chest radiograph performed after repatriation was consistent with a large left pleural effusion, but bedside ultrasound showed a lobulated mass involving the left hemidiaphragm. A pleural procedure in the traditional 'triangle of safety' would have resulted in inadvertent puncture of the underlying mass. Serial imaging confirmed the mass was rapidly progressing, and metastatic malignant mixed Mullerian endometrial carcinoma was diagnosed by endobronchial biopsy. A tunnelled intrapleural catheter was inserted for symptom relief, and the patient deteriorated and died at home 2 weeks later. To our knowledge, this is the first case of endobronchial metastasis from malignant mixed Mullerian tumour of the uterus.

http://ift.tt/2pUbtar

Intramural oesophageal haematoma following traumatic neck injury

This case describes a previously well 90-year-old woman who presented with neck pain, swelling, dysphagia and hoarseness following a motor vehicle collision. Oesophageal oedema was visualised on CT of cervical spine and subsequent CT angiography highlighted an actively bleeding intramural oesophageal haematoma (IOH) extending from the cervical oesophagus to the carina. This rare phenomenon (IOH) has been described as a possible consequence of blunt trauma to the neck; however, we found no cases resulting from acceleration/deceleration injury. Although this was a potentially life-threatening injury, our patient made a full recovery with conservative management.

http://ift.tt/2EbWThC

The 2-anilino-4-amino-5-aroylthiazole-type compound AS7128 inhibits lung cancer growth through decreased iASPP and p53 interaction

Abstract

Lung cancer is the leading cause of cancer-related death worldwide. Thus, developing novel therapeutic agents become urgent demands for lung cancer treatment. In this study, compound AS7128 was selected from a two-million entry chemical library screening and identified as a candidate drug that against non-small cell lung cancer (NSCLC) in vitro and in vivo. Further investigation indicated that AS7128 could induce cell apoptosis and cell cycle arrest, especially in the mitosis stage. In addition, we also found that iASPP, an oncogenic protein that functionally inhibits p53, might be associated with AS7128 through mass identification. Further exploration indicated that AS7128 treatment could restore the transactivation ability of p53 and thus increase the expressions of its downstream target genes, which are related to cell cycle arrest and apoptosis. This occurs via disruption of the interactions between p53 and iASPP in cells. Taken together, AS7128 could bind to iASPP, disrupt the interaction between iASPP and p53, and result in cell cycle arrest and apoptosis. These findings may provide new insights for using iASPP as a therapeutic target for NSCLC treatment.

This article is protected by copyright. All rights reserved.

http://ift.tt/2zKnAH5

Exosomes Serve as Nano-particles to Suppress Tumor Growth and Angiogenesis in Gastric Cancer by Delivering HGF siRNA

Abstract

Exosomes derived from cells have been found to mediate signal transduction between cells and to act as efficient carriers to deliver drugs and small RNAs. HGF is known to promote the growth of both cancer cells and vascular cells, and the HGF-cMET pathway is a potential clinical target. Here, we characterized the inhibitory effect of HGF siRNA on tumor growth and angiogenesis in gastric cancer. In addition, we showed that HGF siRNA packed in exosomes can be transported into cancer cells, where it dramatically down-regulates HGF expression. A cell co-culture model was used to show that exosomes loaded with HGF siRNA suppress proliferation and migration of both cancer cells and vascular cells. Moreover, exosomes were able to transfer HGF siRNA in vivo, decreasing the growth rates of tumors and blood vessels. The results of our study demonstrate that exosomes have potential for use in targeted cancer therapy by delivering siRNAs.

This article is protected by copyright. All rights reserved.

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C-C chemokine receptor type 1 mediates osteopontin-promoted metastasis in hepatocellular carcinoma

Abstract

In hepatocellular carcinoma (HCC) microenvironment, chemokine receptors have a critical role in tumorigenesis and metastasis. Our previous studies have found that osteopontin (OPN) is a promoter for HCC metastasis. However, the role of chemokine receptors in OPN-induced HCC metastasis still remains unclear. In this study, we demonstrate that OPN is dramatically elevated in HCC tissues with metastasis and high expression of OPN correlates with poorer overall survival and higher recurrence rate. OPN upregulates chemokine receptor expression, migration, invasion, and pulmonary metastasis in HCC. We find that C-C chemokine receptor type 1 (CCR1) and C-X-C chemokine receptor type 6 (CXCR6) are the most upregulated chemokine receptors induced by OPN. CCR1 knockdown results in reduction of migration, invasion and pulmonary metastasis induced by OPN in vitro and in vivo, whereas CXCR6 knockdown does not reverse OPN-promoted migration and invasion. Moreover, OPN up-regulates the expression of CCR1 via activating phosphoinositide 3-kinase (PI3K)/AKT and hypoxia-inducible factor 1α (HIF-1α) in HCC cells. Furthermore, blockade of OPN-CCR1 axis with CCR1 antagonist significantly restrains the promoting effects of OPN on HCC progression and metastasis. In human HCC tissues, OPN expression shows significantly positive correlation with CCR1 expression, and the patients with high levels of both OPN and CCR1 have the most dismal prognosis. Collectively, our results indicate that the OPN-CCR1 axis in HCC is important for accelerating tumor metastasis and CCR1 is a potential therapeutic target for controlling metastasis in HCC patients with high OPN.

This article is protected by copyright. All rights reserved.

http://ift.tt/2zKSHlB

Implementation of “Clinical Sequencing” in Cancer Genome Medicine in Japan

Abstract

In oncology, actionable mutations (alterations) in cancer-associated genes are critical in terms of the selection of therapeutic approaches. Next-generation sequencing (NGS) of tumor sample DNA (i.e., clinical sequencing) can guide clinical management by providing diagnostic or prognostic data, and facilitating the identification of potential treatment regimens, such as molecular-targeted and immune checkpoint blockade therapies. In the U.S., a variety of tumor-profiling multiplex gene panels have been developed and implemented for this purpose. In Japan, several academic institutions have now performed detailed investigations of the feasibility and value of clinical sequencing, and cancer societies have issued consensus clinical practice guidelines for NGS-based gene panel tests. These efforts will facilitate the implementation of cancer genome medicine in Japan.

This article is protected by copyright. All rights reserved.

http://ift.tt/2C6HEJr

Cancer Immunotherapy Targeted Glypican-3 or Neoantigens

Abstract

Immune checkpoint inhibitors have ushered a new era in cancer therapy, although other therapies or combinations thereof are still needed for the many patients for whom these drugs are ineffective. In this light, we have identified in glypican-3 an HLA-24, HLA-A2 restriction peptide with extreme cancer specificity. In this paper, we summarize results from a number of related clinical trials demonstrating that glypican-3 peptide vaccines induce specific cytotoxic T lymphocytes in most patients (UMIN Clinical Trials Registry: UMIN000001395, UMIN000005093, UMIN000002614, UMN000003696, UMIN000006357,). We also describe the current state of personalized cancer immunotherapy based on neoantigens, and assess, based on our own research and experience, the potential of such therapy to elicit cancer regression. Finally, we discuss the future direction of cancer immunotherapy.

This article is protected by copyright. All rights reserved.

http://ift.tt/2zLet90

Proposal for Reclassification of N Staging Systems in Penile Cancer Patients: Based on Number of Positive Lymph Nodes

Abstract

In the present study, we aim to compare the rationality of proposed N classification based on the number of metastatic lymph nodes (LNs) with the current one. A total of 509 penile cancer patients at our institute were analyzed. Univariable and multivariable statistical analyses were used to assess cancer-specific survival (CSS) in two staging systems. Harrell's concordance index was applied to evaluate predictive accuracy of the current and proposed N classification in predicting CSS. We propose a new classification: pN1 (metastasis in 1-2 regional LNs), pN2 (metastasis in 3 regional LNs, or three or fewer regional lymph nodes with extranodal extension), and pN3 (metastasis in 4 or more regional LNs). According to the current and proposed N classification, the five-year CSS of penile cancer patients with pN1, pN2 and pN3 was 85.8%, 39.0%, and 19.7%; and with pN1, pN2 and pN3 was 79.8%, 39.3% and 15.3%, which almost all showed significant difference (P < 0.001, P = 0.259) (P < 0.001, P < 0.001). Multivariable predictive accuracy of the proposed and current N staging was 76.48% and 70.92% (5.56% gain; P < 0.001). With a multivariable model of clinical features, both current (hazard ratio [HR], 7.761, 10.612; P < 0.001, P < 0.001) and proposed N stages (HR, 3.792, 3.971; P < 0.001, P < 0.001) exhibited independent effects on survival. The proposed N classification is superior to the current one, which is simpler and provides more accurate prognosis.

This article is protected by copyright. All rights reserved.

http://ift.tt/2C7pt6L

Regulatory mechanisms of HIF-1 activity: Two decades of knowledge

Abstract

Hypoxia-inducible factor 1 (HIF-1) is a transcriptional activator of various genes related to cellular adaptive responses to hypoxia. Dysfunctions in the regulatory systems of HIF-1 activity have been implicated in the pathogenesis of various diseases including malignant tumors, and, thus, elucidating the molecular mechanisms underlying the activation of HIF-1 is eagerly desired for the development of novel anti-cancer strategies. The importance of the oxygen-dependent and ubiquitin-mediated proteolysis of the regulatory subunit of HIF-1 (HIF-1α) was first reported in 1997. Since then, accumulating evidence has revealed that HIF-1α may become stable and active, even under normoxic conditions; e.g. when disease-associated genetic and functional alterations in some genes trigger the aberrant activation of HIF-1 regardless of the oxygen conditions. We herein review the last two decades of knowledge, since 1997, on the regulatory mechanisms of HIF-1 activity from conventional oxygen- and proteolysis-dependent mechanisms to up-to-the-minute information on cancer-associated genetic and functional alteration-mediated mechanisms.

This article is protected by copyright. All rights reserved.

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The new metformin derivative HL156A prevents oral cancer progression by inhibiting the IGF/Akt/mTOR pathways

Summary

Metformin is a biguanide widely prescribed as an antidiabetic drug for type 2 diabetes mellitus patients. The purpose of this study was to observe the effects of the new metformin derivative, HL156A, on human oral cancer cell and to investigate its possible mechanisms. It was observed that HL156A significantly decreased FaDu and YD-10B cell viability and colony formation in a dose dependent manner. HL156A also markedly reduced wound closure and migration of FaDu and YD-10B cells. We observed that HL156A decreased mitochondrial membrane potential and induced ROS levels and apoptotic cells with caspase-3 and -9 activation. HL156A inhibited the expression and activation of IGF-1 and its downstream proteins, AKT, mTOR, and ERK1/2. In addition, HL156A activated AMPK-NF-κB signaling of FaDu and YD-10B cells. A xenograft mouse model further revealed that HL156A suppressed AT84 mouse oral tumor growth, accompanied by downregulated p-IGF-1, p-mTOR, PCNA and promoted p-AMPK and TUNEL expression. These results suggest the potential value of the new metformin derivative HL156A as a candidate for a therapeutic modality for the treatment of oral cancer.

This article is protected by copyright. All rights reserved.

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Nimotuzumab combined with concurrent chemoradiotherapy in Japanese patients with esophageal cancer: a phase I study

Summary

Nimotuzumab is a humanized anti-epidermal growth factor receptor IgG1 monoclonal antibody. This phase I study assessed the tolerability, safety, efficacy, and PK of nimotuzumab in combination with chemoradiotherapy in Japanese patients with esophageal cancer. Patients with stage II, III, and IV esophageal cancer were enrolled. Patients were planned to receive nimotuzumab (level 1: 200 mg/week for 25 weeks; or level 2: 400 mg/week in the chemoradiation period, 400 mg biweekly in an additional chemotherapy period [8 weeks after the chemoradiation period] and a maintenance therapy period [after chemotherapy to 25 weeks]) combined with cisplatin (75 mg/m² on day 1) and fluorouracil (1000 mg/m² on days 1 to 4) in the chemoradiation and additional chemotherapy periods. Radiotherapy was administered concurrently at 50.4 Gy. A total of 10 patients were enrolled in level 1. Dose-limiting toxicities were observed in two patients (grade 3 infection and renal disorder). The maximum tolerated dose was estimated to be at least 200 mg/week and the dose was not escalated to level 2. The most common grade ≥3 toxicities were lymphopenia (90%), leukopenia (60%), neutropenia (50%), and febrile neutropenia, decreased appetite, hyponatremia, and radiation esophagitis (30% each). Neither treatment-related death nor grade ≥3 skin toxicity was observed in any patient. Complete response rate was 50%. Progression-free survival was 13.9 months. One- and 3-year survival rates were 75% and 37.5%, respectively. Immunogenicity was not reported in any patient. Nimotuzumab in combination with concurrent chemoradiotherapy was tolerable and effective for Japanese patients with esophageal cancer.

This article is protected by copyright. All rights reserved.

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Altered motor plasticity in an acute relapse of multiple sclerosis

Abstract

In relapsing-remitting MS (RRMS) the symptoms of a clinical relapse subside over time. Neuroplasticity is believed to play an important compensatory role. In this study we assessed excitability-decreasing plasticity during an acute relapse of MS and 12 weeks afterwards. Motor plasticity was examined in 19 patients with clinically isolated syndrome or RRMS during a steroid-treated relapse (t1) and 12 weeks afterwards (t2) using paired-associative stimulation (PAS10). This method combines repetitive electric nerve stimulation with transcranial magnetic stimulation of the contralateral motor cortex to model long-term synaptic depression in the human cortex. Additionally, 19 age-matched healthy controls were assessed. Motor evoked potentials of the abductor pollicis brevis muscle were recorded before and after intervention. Clinical disability was assessed by the Multiple Sclerosis Functional Composite and the subscore of the nine-hole peg test taken as a measure of hand function. The effect of PAS10 was significantly different between controls and patients: At t1, but not at t2, baseline-normalized postinterventional amplitudes were significantly higher in patients (106 [IQR 98 – 137] % post10-15 and 111 [IQR 88-133] % post20-25) compared to controls (92 [IQR 85-111] % and 90 [IQR 75-102] %). Additional exploratory analysis indicated a potentially excitability-enhancing effect of PAS10 in patients as opposed to controls. Significant clinical improvement between t1 and t2 was not correlated with PAS10 effects.

Our results indicate an alteration of PAS10-induced synaptic plasticity during relapse, presumably reflecting a polarity shift due to metaplastic processes within the motor cortex. Further studies will need to elucidate the functional significance of such changes for the clinical course of MS.

This article is protected by copyright. All rights reserved.

http://ift.tt/2pTkYa6

Identifying and understanding the health and social care needs of older adults with multiple chronic conditions and their caregivers: a protocol for a scoping review

Introduction

People are living longer; however, they are not necessarily experiencing good health and well-being as they age. Many older adults live with multiple chronic conditions (MCC), and complex health issues, which adversely affect their day-to-day functioning and overall quality of life. As a result, they frequently rely on the support of friend and/or family caregivers. Caregivers of older adults with MCC often face challenges to their own well-being and also require support. Currently, not enough is known about the health and social care needs of older adults with MCC and the needs of their caregivers or how best to identify and meet these needs. This study will examine and synthesise the literature on the needs of older adults with MCC and those of their caregivers, and identify gaps in evidence and directions for further research.

Methods and analysis

We will conduct a scoping review of the peer-reviewed and grey literature using the updated Arksey and O'Malley framework. The literature will be identified using a multidatabase and grey literature search strategy developed by a health sciences librarian. Papers, reports and other materials addressing the health and social care needs of older adults and their friend/family caregivers will be included. Search results will be screened, independently, by two reviewers, and data will be abstracted from included literature and charted in duplicate.

Ethics and dissemination

This scoping review does not require ethics approval. We anticipate that study findings will inform novel strategies for identifying and ascertaining the health and social care needs of older adults living with MCC and those of their caregivers. Working with knowledge-user members of our team, we will prepare materials and presentations to disseminate findings to relevant stakeholder and end-user groups at local, national and international levels. We will also publish our findings in a peer-reviewed journal.

http://ift.tt/2ChxOnu

Research protocol for the Picture Talk Project: a qualitative study on research and consent with remote Australian Aboriginal communities

Introduction

Research with Indigenous populations is not always designed with cultural sensitivity. Few publications evaluate or describe in detail seeking consent for research with Indigenous participants. When potential participants are not engaged in a culturally respectful manner, participation rates and research quality can be adversely affected. It is unethical to proceed with research without truly informed consent.

Methods and analysis

We describe a culturally appropriate research protocol that is invited by Aboriginal communities of the Fitzroy Valley in Western Australia. The Picture Talk Project is a research partnership with local Aboriginal leaders who are also chief investigators. We will interview Aboriginal leaders about research, community engagement and the consent process and hold focus groups with Aboriginal community members about individual consent. Cultural protocols will be applied to recruit and conduct research with participants. Transcripts will be analysed using NVivo10 qualitative software and themes synthesised to highlight the key issues raised by the community about the research process. This protocol will guide future research with the Aboriginal communities of the Fitzroy Valley and may inform the approach to research with other Indigenous communities of Australia or the world. It must be noted that no community is the same and all research requires local consultation and input. To conduct culturally sensitive research, respected local people from the community who have knowledge of cultural protocol and language are engaged to guide each step of the research process from the project design to the delivery of results.

Ethics and dissemination

Ethics approval was granted by the University of Sydney Human Research Ethics Committee (No. 2012/348, reference:14760), the Western Australia Country Health Service Ethics Committee (No. 2012:15), the Western Australian Aboriginal Health Ethics Committee and reviewed by the Kimberley Aboriginal Health Planning Forum Research Sub-Committee (No. 2012–008). Results will be disseminated through peer review articles, a local Fitzroy Valley report and conference presentations.

http://ift.tt/2BOBd9T

Effectiveness and cost-effectiveness of a guided internet- and mobile-based depression intervention for individuals with chronic back pain: protocol of a multi-centre randomised controlled trial

Introduction

Depression often co-occurs with chronic back pain (CBP). Internet and mobile-based interventions (IMIs) might be a promising approach for effectively treating depression in this patient group. In the present study, we will evaluate the effectiveness and cost-effectiveness of a guided depression IMI for individuals with CBP (eSano BackCare-D) integrated into orthopaedic healthcare.

Methods and analysis

In this multicentre randomised controlled trial of parallel design, the groups eSano BackCare-D versus treatment as usual will be compared. 210 participants with CBP and diagnosed depression will be recruited subsequent to orthopaedic rehabilitation care. Assessments will be conducted prior to randomisation and 9 weeks (post-treatment) and 6 months after randomisation. The primary outcome is depression severity (Hamilton Rating Scale for Depression-17). Secondary outcomes are depression remission and response, health-related quality of life, pain intensity, pain-related disability, self-efficacy and work capacity. Demographic and medical variables as well as internet affinity, intervention adherence, intervention satisfaction and negative effects will also be assessed. Data will be analysed on an intention-to-treat basis with additional per-protocol analyses. Moreover, a cost-effectiveness and cost-utility analysis will be conducted from a societal perspective after 6 months.

Ethics and dissemination

All procedures are approved by the ethics committee of the Albert-Ludwigs-University of Freiburg and the data security committee of the German Pension Insurance (Deutsche Rentenversicherung). The results will be published in peer-reviewed journals and presented on international conferences.

Trial registration number

DRKS00009272; Pre-results.

http://ift.tt/2ChZPv6

Association of individual and neighbourhood socioeconomic status with physical activity and screen time in seventh-grade boys and girls in Berlin, Germany: a cross-sectional study

Objectives

Few studies have explored the impact of neighbourhood socioeconomic status (SES) on health behaviours in youths in Germany. Our aim was to investigate the association of individual and neighbourhood SES with physical activity (PA) and screen time (ST) in students aged 12–13 years in Berlin.

Design

Cross-sectional study.

Setting

Secondary schools (high schools and integrated secondary schools) in Berlin, Germany.

Participants

A total of 2586 students aged 12–13 years (seventh grade).

Main outcome measures

Sociodemographics, anthropometric data and health behaviours were assessed by self-report during classes. Primary outcome was the association of individual and neighbourhood SES with meeting daily PA and exceeding daily ST recommendations. Students' characteristics were described with means or percentages. Comparisons were performed using generalised linear mixed model yielding ORs with 95% CIs.

Results

Mean (±SD) age was 12.5±0.5 years, 50.5% were girls and 34.1% had a migrant background. When adjusting for individual covariates, associations of low versus high individual SES were 0.85 (0.48; 1.52) for PA and 2.08 (1.26; 3.43) for ST. Associations of low versus high neighbourhood SES were 1.76 (1.12; 2.75) for PA and 1.54 (1.10; 2.17) for ST. After additional adjustment for school type and school neighbourhood SES, associations comparing low versus high individual and neighbourhood SES were attenuated for PA (individual SES 0.74 (0.41; 1.33) and neighbourhood SES 1.51 (0.93; 2.46)) and ST (individual SES 1.88 (1.12; 3.14) and neighbourhood SES 1.40(0.98; 2.00).

Conclusions

Lower individual and neighbourhood SES were associated with higher ST. Lower neighbourhood but not individual SES was associated with higher PA. After consideration of school type and school neighbourhood SES associations were attenuated and became insignificant for the relationship between neighbourhood SES, PA and ST. Further research is warranted to unravel the complex relationships between individual SES, neighbourhood SES and school environment to develop more targeted health promotion strategies in the future.

http://ift.tt/2BRYmbo

Systematic evidence review of rates and burden of harm of intravenous admixture drug preparation errors in healthcare settings

Objective

To examine published evidence on intravenous admixture preparation errors (IAPEs) in healthcare settings.

Methods

Searches were conducted in three electronic databases (January 2005 to April 2017). Publications reporting rates of IAPEs and error types were reviewed and categorised into the following groups: component errors, dose/calculation errors, aseptic technique errors and composite errors. The methodological rigour of each study was assessed using the Hawker method.

Results

Of the 34 articles that met inclusion criteria, 28 reported the site of IAPEs: central pharmacies (n=8), nursing wards (n=14), both settings (n=4) and other sites (n=3). Using the Hawker criteria, 14% of the articles were of good quality, 74% were of fair quality and 12% were of poor quality. Error types and reported rates varied substantially, including wrong drug (~0% to 4.7%), wrong diluent solution (0% to 49.0%), wrong label (0% to 99.0%), wrong dose (0% to 32.6%), wrong concentration (0.3% to 88.6%), wrong diluent volume (0.06% to 49.0%) and inadequate aseptic technique (0% to 92.7%)%). Four studies directly compared incidence by preparation site and/or method, finding error incidence to be lower for doses prepared within a central pharmacy versus the nursing ward and lower for automated preparation versus manual preparation. Although eight studies (24%) reported ≥1 errors with the potential to cause patient harm, no study directly linked IAPE occurrences to specific adverse patient outcomes.

Conclusions

The available data suggest a need to continue to optimise the intravenous preparation process, focus on improving preparation workflow, design and implement preventive strategies, train staff on optimal admixture protocols and implement standardisation. Future research should focus on the development of consistent error subtype definitions, standardised reporting methodology and reliable, reproducible methods to track and link risk factors with the burden of harm associated with these errors.

http://ift.tt/2BQ5l4x

Pilot for the Australian Breast Device Registry (ABDR): a national opt-out clinical quality registry for breast device surgery

Purpose

To establish a pilot clinical quality registry (CQR) to monitor the quality of care and device performance for breast device surgery in Australia.

Participants

All patients having breast device surgery from contributing hospitals in Australia. A literature review was performed which identified quality indicators for breast device surgery.

Findings to date

A pilot CQR was established in 2011 to capture prospective data on breast device surgery. An interim Steering Committee and Management Committee were established to provide clinical governance, and guide quality indicator selection. The registry's minimum dataset was formulated in consultation with stakeholder groups; potential quality indicators were assessed in terms of (1) importance and relevance, (2) usability, (3) feasibility to collect and (4) scientific validity. Data collection was by a two-sided paper-based form with manual data entry. Seven sites were recruited, including one public hospital, four private hospitals and two day surgeries. Patients were recruited and opt-out consent used.

Future plans

The pilot breast device registry provides high-quality population-based data. It provides a model for developing a national CQR for breast devices; its minimum dataset and quality indicators reflect the opinions of the broad range of stakeholders. It is easily scalable, and has formed the basis for other international surgical groups establishing similar registries.

http://ift.tt/2ChxULS

Applicability of evidence from previous systematic reviews on immunotherapy in current practice of childhood asthma treatment: a GRADE (Grading of Recommendations Assessment, Development and Evaluation) systematic review

Objective

Because most children with asthma now use inhaled corticosteroids (ICS), the added benefit of immunotherapy in asthmatic children needs to be examined. We re-assessed the effectiveness of subcutaneous (SCIT) and sublingual immunotherapy (SLIT) in childhood asthma treatment focusing on studies with patient-relevant outcome measures and children using ICS.

Methods

We used the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach to systematically search and appraise the evidence using predefined critical patient-relevant outcomes (asthma symptoms, asthma control and exacerbations). We searched to retrieve systematic reviews and randomised controlled trials on immunotherapy for asthma in children (1960–2017). We assessed the quality of the body of evidence with GRADE criteria.

Results

The quality of the evidence for SCIT was very low due to a large risk of bias and indirectness (dated studies in children not using ICS). No effect of SCIT was found for asthma symptoms; no studies reported on asthma control. For asthma exacerbations, studies favoured SCIT. We have little confidence in this effect estimate, due to the very low quality of evidence. For SLIT, quality of the evidence was very low due to a large risk of bias, indirectness and imprecision. The outcome 'asthma symptoms' could not be calculated due to lack of standardisation and large clinical heterogeneity. Other predefined outcomes were not reported.

Conclusion

The beneficial effects of immunotherapy in childhood asthma found in earlier reviews are no longer considered applicable, because of indirectness (studies performed in children not being treated according to current asthma guidelines with ICS). There was absence of evidence to properly determine the effectiveness or lack thereof of immunotherapy in asthma treatment in children with ICS.

http://ift.tt/2BRuX16

Do biological disease-modifying antirheumatic drugs reduce the spinal fracture risk related to ankylosing spondylitis? A longitudinal multiregistry matched cohort study

Objectives

Ankylosing spondylitis (AS) is associated with an increased spinal fracture risk due to the loss of elasticity in spinal motion segments. With the introduction of biological disease-modifying antirheumatic drug (bDMARD) treatment for AS, the individual course of the disease has been ameliorated. This study aims to examine the association of bDMARD treatment and risk of spinal fracture.

Design

Longitudinal population-based multiregistry observational matched cohort study.

Setting

Swedish Patient Registry 1987–2014 and Swedish Prescribed Drugs Registry 2005–2014.

Participants

Included were patients ≥18 years of age receiving treatment at a healthcare facility for the primary diagnosis of AS. About 1352 patients received more than one prescription of bDMARD from 2005 to 2014. An untreated control group was created by propensity score matching for age, sex, comorbidity, antirheumatic prescriptions and years with AS (n=1352).

Main outcome measures

Spinal fracture-free survival.

Results

No bDMARD treatment-related effect on spinal fracture-free survival was observed in the matched cohorts. Male gender (HR=2.54, 95% CI 1.48 to 4.36) and Charlson Comorbidity Index score (HR=3.02, 95% CI 1.59 to 5.75) contributed significantly to spinal fracture risk.

Conclusion

bDMARD had no medium-term effect on the spinal fracture-free survival in patients with AS.

Trial registration number

NCT02840695; Post-results.

http://ift.tt/2BRAAfC

Implementation of a lung cancer multidisciplinary team standardised template for reporting to general practitioners: a mixed-method study

Objectives

Few interventions have been designed that provide standardised information to primary care clinicians about the diagnostic and treatment recommendations resulting from cancer multidisciplinary team (MDT) (tumour board) meetings. This study aimed to develop, implement and evaluate a standardised template for lung cancer MDTs to provide clinical information and treatment recommendations to general practitioners (GPs). Specific objectives were to (1) evaluate template feasibility (acceptability, appropriateness and timeliness) with GPs and (2) document processes of preimplementation, implementation and evaluation within the MDT setting.

Design

A mixed-method study design using structured interviews with GPs and qualitative documentation of project logs about implementation processes.

Setting

Two hospitals in Central Sydney, New South Wales, Australia. Participants: 61 GPs evaluated the template. Two lung cancer MDTs, consisting of 33 clinicians, and eight researchers participated in template development and implementation strategy.

Results

The MDT-reporting template appears to be a feasible way of providing clinical information to GPs following patient presentation at a lung cancer MDT meeting. Ninety-five per cent of GPs strongly agreed or agreed that the standardised template provided useful and relevant information, that it was received in a timely manner (90%) and that the information was easy to interpret and communicate to the patient (84%). Implementation process data show that the investment made in the preimplementation stage to integrate the template into standard work practices was a critical factor in successful implementation.

Conclusions

This study demonstrates that it is feasible to provide lung cancer MDT treatment recommendations to GPs through implementation of a standardised template. A simple intervention, such as a standardised template, can help to address quality gaps and ensure that timely information is communicated between tertiary and primary care healthcare providers.

http://ift.tt/2BRpIyi

Long-term early development research in congenital heart disease (LEADER-CHD): a study protocol for a prospective cohort observational study investigating the development of children after surgical correction for congenital heart defects during the first 3 years of life

Introduction

Congenital heart disease (CHD) is the most common birth defect. Studies on the development of children with CHD point towards deficits in motoric, cognitive and language development. However, most studies are cross-sectional and there is a gap in the knowledge concerning developmental trajectories, risk and protective factors and a lack of research concerning environmental predictors. Specifically, no studies have so far considered the importance of early caregiving experiences and child temperament for the development of children with CHD.

Methods

In a single-centre prospective cohort study, cognitive, motoric and language development of 180 children after corrective surgery for a simple transposition of the great arteries (TGA), tetralogy of Fallot (TOF) or ventricular septal defect (VSD) will be assessed at ages 12, 24 and 36 months with the Bayley Scales of Infant Development 3rd Edition (BSID-III). At age 12 months, a free-play video observation will be conducted to investigate the relationship between primary caregiver and child, and child temperament will be assessed with the Infant Behavior Questionnaire—Revised Short Version. Medical information will be obtained from patient records and demographic information via questionnaires.

Analysis

Frequency and severity of developmental delays will be reported descriptively. Differences between groups (TGA, TOF, VSD) will be subjected to repeated-measures analysis across time points. Multiple regressions will be applied for the analysis of predictors at each time point. For the analysis of differential developmental trajectories, mixed-model analysis will be applied.

Ethics and dissemination

The study has been approved by the local medical ethics committee. Written informed consent will be obtained from all participants. Parents have the option to be debriefed about BSID-III results after each assessment and about the study results after project completion. Results will be disseminated in peer-reviewed journals and presented at conferences.

Trial registration number

DRKS00011006; Pre-results.

http://ift.tt/2ChkkrN

The renal parenchyma--evaluation of a novel ultrasound measurement to assess fetal renal development: protocol for an observational longitudinal study

Introduction

Disorders of fetal growth, such as intrauterine growth restriction (IUGR) and large for gestational age (LGA), have been found to have a profound effect on the development of the fetal kidney. Abnormal kidney development is associated with hypertension and chronic kidney disease later in life. This study will use a novel ultrasound measurement to assess the renal parenchymal growth and kidney arterial blood flow in the fetus to evaluate the development of the fetal kidneys and provide an indirect estimate of nephron number. Measurements in normally grown, IUGR and LGA fetuses will be compared to determine if changes in renal parenchymal growth can be detected in utero.

Methods and analysis

This longitudinal, prospective, observational study will be conducted over 12 months in the Ultrasound Department of the Townsville Hospital, Australia. The study will compare fetal renal parenchymal thickness (RPT) and renal artery Doppler flow between IUGR fetuses and appropriately grown fetuses, and LGA fetuses and appropriately grown fetuses between 16 and 40 weeks. The fetal RPT to renal volume ratio will also be compared, and correlations between RPT, renal parenchymal echogenicity, fetal Doppler indices and amniotic fluid levels will be analysed.

Ethics and dissemination

This study was approved by the Townsville Health District Human Research Ethics Committee. The study results will form part of a thesis and will be published in peer-reviewed journals and disseminated at international conferences.

http://ift.tt/2ChgOO3

Association of occasional smoking with total mortality in the population-based Tromso study, 2001-2015

Objectives

There is a shift in the smoking population from daily smokers to light or occasional smokers. The knowledge about possible adverse health effects of this new smoking pattern is limited. We investigated smoking habits with focus on occasional smoking in relation to total mortality in a follow-up study of a Norwegian general population.

Setting

A population study in Tromsø, Norway.

Methods

We collected smoking habits and relevant risk factors in 4020 women and 3033 men aged 30–89 years in the Tromsø Study in 2001. The subjects were followed up regarding total mortality through June 2015.

Results

Among the participants, there were 7% occasional smokers. Occasional smokers were younger, more educated and used alcohol more frequently than other participants. A total of 766 women and 882 men died during the follow-up. After the adjustment for confounders, we found that occasional smoking significantly increased mortality by 38% (95% CI 8% to 76%) compared with never smokers. We report a dose–response relationship in the hazards of smoking (daily, occasional, former and never smoking).

Conclusions

Occasional smoking is not a safe smoking alternative. There is a need for information to the general public and health workers about the health hazards of occasional smoking. More work should be done to motivate this often well-educated group to quit smoking completely.

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Can we Save the rectum by watchful waiting or TransAnal microsurgery following (chemo) Radiotherapy versus Total mesorectal excision for early REctal Cancer (STAR-TREC study)?: protocol for a multicentre, randomised feasibility study

Introduction

Total mesorectal excision (TME) is the highly effective standard treatment for rectal cancer but is associated with significant morbidity and may be overtreatment for low-risk cancers. This study is designed to determine the feasibility of international recruitment in a study comparing organ-saving approaches versus standard TME surgery.

Methods and analysis

STAR-TREC trial is a multicentre international randomised, three-arm parallel, phase II feasibility study in patients with biopsy-proven adenocarcinoma of the rectum. The trial is coordinated from Birmingham, UK with national hubs in Radboudumc (the Netherlands) and Odense University Hospital Svendborg UMC (Denmark). Patients with rectal cancer, staged by CT and MRI as ≤cT3b (up to 5 mm of extramural spread) N0 M0 can be included. Patients will be randomised to either standard TME surgery (control), organ-saving treatment using long-course concurrent chemoradiation or organ-saving treatment using short-course radiotherapy. For patients treated with an organ-saving strategy, clinical response to (chemo)radiotherapy determines the next treatment step. An active surveillance regime will be performed in the case of a complete clinical regression. In the case of incomplete clinical regression, patients will proceed to local excision using an optimised platform such as transanal endoscopic microsurgery or other transanal techniques (eg, transanal endoscopic operation or transanal minimally invasive surgery). The primary endpoint of this phase II study is to demonstrate sufficient international recruitment in order to sustain a phase III study incorporating pelvic failure as the primary endpoint. Success in phase II is defined as randomisation of at least four cases per month internationally in year 1, rising to at least six cases per month internationally during year 2.

Ethics and dissemination

The medical ethical committees of all the participating countries have approved the study protocol. Results of the primary and secondary endpoints will be submitted for publication in peer-reviewed journals.

Trial registration number

ISRCTN14240288, 20 October 2016. NCT02945566; Pre-results, October 2016.

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Exercise and adiposity in overweight and obese children and adolescents: protocol for a systematic review and network meta-analysis of randomised trials

Introduction

Overweight and obesity is a worldwide public health problem among children and adolescents. However, the magnitude of effect, as well as hierarchy of exercise interventions (aerobic, strength training or both), on selected measures of adiposity is not well established despite numerous trials on this issue. The primary purposes of this study are to use the network meta-analytical approach to determine the effects and hierarchy of exercise interventions on selected measures of adiposity in overweight and obese children and adolescents.

Methods and analysis

Randomised exercise intervention trials >4 weeks, available in any language up to 31 August 2017 and which include direct and/or indirect evidence, will be included. Studies will be located by searching seven electronic databases, cross-referencing and expert review. Dual selection and abstraction of data will occur. The primary outcomes will be changes in body mass index (in kg/m²), fat mass and percent body fat. Risk of bias will be assessed using the Cochrane Risk of Bias assessment instrument while confidence in the cumulative evidence will be assessed using the Grading of Recommendations Assessment, Development and Evaluation instrument for network meta-analysis. Network meta-analysis will be performed using multivariate random-effects meta-regression models. The surface under the cumulative ranking curve will be used to provide a hierarchy of exercise treatments (aerobic, strength or both).

Ethics and dissemination

This study does not require ethics approval. Findings will be presented at a professional conference and published in a peer-reviewed journal.

PROSPERO registration number

CRD 42017073103.

http://ift.tt/2BP2E3f

Phenotype and genotype of muscle ryanodine receptor rhabdomyolysis-myalgia syndrome

Objectives

Rhabdomyolysis and myalgia are common conditions, and mutation in the ryanodine receptor 1 gene (RYR1) is suggested to be a common cause. Due to the large size of RYR1, however, sequencing has not been widely accessible before the recent advent of next-generation sequencing technology and limited phenotypic descriptions are therefore available.

Material & Methods

We present the medical history, clinical and ancillary findings of patients with RYR1 mutations and rhabdomyolysis and myalgia identified in Denmark, France and The Netherlands.

Results

Twenty-two patients with recurrent rhabdomyolysis (CK > 10 000) or myalgia with hyperCKemia (>1.5 × ULN) and a RYR1 mutation were identified. One had mild wasting of the quadriceps muscle, but none had fixed weakness. Symptoms varied from being restricted to intense exercise to limiting ADL function. One patient developed transient kidney failure during rhabdomyolysis. Two received immunosuppressants on suspicion of myositis. None had episodes of malignant hyperthermia. Muscle biopsies were normal, but CT/MRI showed muscle hypertrophy in most. Delay from first symptom to diagnosis was 12 years on average. Fifteen different dominantly inherited mutations were identified. Ten were previously described as pathogenic and 5 were novel, but rare/absent from the background population, and predicted to be pathogenic by in silico analyses. Ten of the mutations were reported to give malignant hyperthermia susceptibility.

Conclusion

Mutations in RYR1 should be considered as a significant cause of rhabdomyolysis and myalgia syndrome in patients with the characteristic combination of rhabdomyolysis, myalgia and cramps, creatine kinase elevation, no weakness and often muscle hypertrophy.

http://ift.tt/2zKacm4

Prognostic values of the integrated model incorporating the volume of metastatic regional cervical lymph node and pretreatment serum Epstein–Barr virus DNA copy number in predicting distant metastasis in patients with N1 nasopharyngeal carcinoma

According to the 7th edition of the American Joint Committee on Cancer (AJCC) staging system, over 50% of patients with nasopharyngeal carcinoma (NPC) have N1 disease at initial diagnosis. However, patients wi...

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Formal models and quantitative measures of multisensory integration: a selective overview

Abstract

Multisensory integration (MI) is defined as the neural process by which unisensory signals are combined to form a new product that is significantly different from the responses evoked by the modality-specific component stimuli. In recent years, MI research has seen exponential growth in the number of empirical and theoretical studies. This paper presents a selective overview of formal modeling approaches to MI. Emphasis is on models and measures for behavioral paradigms like, e.g., localization, judgment of temporal order or simultaneity, and reaction times, but some concepts for the modeling of single cell spike rates are treated as well. We identify a number of essential concepts underlying most model classes, like Bayesian causal inference, probability summation, coactivation, and time window of integration. Quantitative indexes for measuring and comparing the strength of MI across different paradigms are also discussed. Whereas progress over the last years is remarkable, we point out some strengths and weaknesses of the modeling approaches and discuss some obstacles towards a unified theory of MI.

This article is protected by copyright. All rights reserved.

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Low-virulent Babesia venatorum infection masquerading as hemophagocytic syndrome

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Editorial Board

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Potential demographic, clinical, and environment risk factors for canine visceral leishmaniasis using IFAT and nested PCR, southeastern Iran

Abstract

Visceral leishmaniasis (VL) is a fatal disease with major veterinary and medical impacts. In the present study, we investigated the significance of potential demographic, clinical, and environmental risk factors for canine VL (CVL), southeastern Iran. This study was performed between 2014 and 2015 on 210 randomly selected stray dogs which were caught by live traps. A 5 ml blood sample was taken from cephalic vein for indirect immunofluorescence antibody test (IFAT) and nested PCR. The cut-off titer for IFAT was 1:320. For molecular test, two sets of general and specific primers were used to amplify variable mini circle region of kinetoplast DNA (kDNA). Data analyses were performed by x ² and logistic regression tests at P < 0.05. Overall, 210 dogs consisting of 87 males and 123 females were examined and 14 dogs (6.7%) were considered infected with VL. Age < 2 years (OR = 14.106, CI = 1.810–109.924, P = 0.012); short hair (OR = 15.311 CI = 1.965–119.324, P = 0.009); solid waste (OR = 0.050 CI = 0.006–0.388, P = 0.004); weather with water, clouds, and creek (OR = 0.089, CI = 0.011–0.692, P = 0.021); and nearby dog present (OR = 0.065, CI 0.008–0.509, P = 0.009) were the major risk factors associated with CVL. In contrast, sex, tick infested, meadow, and clinical signs were negatively associated odds of infection. Control approaches should be directed toward specific demographic and environmental factors to reduce the risk of CVL in the area.

http://ift.tt/2ldwbNZ

Choice of postoperative radiation for stage IIIA pathologic N2 non-small cell lung cancer: impact of metastatic lymph node number

Abstract

Background

Postoperative radiation (PORT) is an option for non-small cell lung cancer (NSCLC) patients with resectable stage IIIA pathological N2 status (pN2). For patients with PORT, this study aims to investigate the impact of the exact number of positive lymph nodes (LNs) on overall survival (OS) and lung cancer-specific survival (LCSS).

Methods

Within the Surveillance, Epidemiology, and End Results database, we identified 3373 patients with stage IIIA pathological N2 status (pN2) NSCLC who underwent a lobectomy or pneumonectomy from 2004 to 2013. OS and LCSS were compared among patients coded as receiving PORT or observation. The proportional hazards model was applied for investigation.

Results

OS and LCSS favored PORT for patients with stage IIIA (pN2) NSCLC. Multivariable analyses showed that PORT and the exact number of positive LNs (n ≤ 3) were independently associated with better OS and LCSS. Both better OS and LCSS emerged for positive LNs (n > 3) after the use of PORT in survival analyses, whereas the benefits of OS and LCSS were not observed anymore for positive LNs (n ≤ 3) group. More importantly, multivariable analyses showed that the use of PORT is an independent risk factor of survival for positive LNs (n > 3) but not for positive LNs (n ≤ 3).

Conclusions

In Stage IIIA (pN2) NSCLC, the use of PORT demonstrated better survival results than no PORT for patients with positive LNs (n > 3), but not for patients with positive LNs (n ≤ 3).

http://ift.tt/2zKeGsO

The effect of selective internal radiation therapy with yttrium-90 resin microspheres on lung carbon monoxide diffusion capacity

Abstract

Background

Selective internal radiation therapy (SIRT) with embolization of branches of the hepatic artery is a valuable therapeutic tool for patients with hepatic malignancies; however, it is also associated with lung injury risk due to shunting. Diffusion capacity of the lungs for carbon monoxide (DLCO) is a clinically significant lung function test, and worsening in DLCO is suggested to reflect a limited gas exchange reserve caused by the potential toxicity of chemoradiotherapy or it may be a marker of related lung injury. This study aimed to examine the changes in DLCO during SIRT with resin microspheres in newly treated and retreated patients. Forty consecutive patients who received SIRT for a variety of malignant conditions were included. All subjects were treated with Yttrium-90 labelled resin microspheres. DLCO tests were performed after the procedures. In addition, patients were specifically followed for radiation pneumonitis.

Results

The mean DLCO did not significantly change after the first (82.8 ± 19.4 vs. 83.1 ± 20.9, p = 0.921) and the second treatments (87.4 ± 19.7 vs. 88.6 ± 23.2, p = 0.256). Proportion of patients with impaired DLCO at baseline was not altered significantly after the first (37.5 vs. 45.0%, p = 0.581) and the second treatments (27.3 vs. 27.3%, p = 1.000). Also, percent change in DLCO values did not correlate with radiation dose, lung shunt fraction, or lung exposure dose (p > 0.05 for all comparisons). None of the patients developed radiation pneumonitis.

Conclusions

Our results suggest that no significant change in DLCO in association with SIRT occurs, both after the first or the second treatment sessions. Further larger studies possibly with different protocols are warranted to better delineate DLCO changes after SIRT in a larger spectrum of patients.

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High CEA levels in a case of resected colorectal cancer: delayed diagnosis of metachronous medullary thyroid cancer

Abstract

Background

Carcinoembryonic antigen (CEA) is one of the most widely used tumor markers, and its value in the surveillance of post-operative colorectal cancer is well established. Fluorodeoxyglucose-positron emission tomography (FDG-PET) has been clinically used in colorectal cancer imaging including preoperative staging, evaluation of therapeutic response, detection of disease recurrence, and investigation of unexplained rising tumor markers.

Case presentation

We report a case of resected colorectal cancer presented with rising CEA levels in 5 years, and FDG-PET revealed no definitive evidence of recurrence except abnormal focal FDG uptake in the right thyroid lobe. However, fine needle aspiration cytology (FNAC) of the thyroid nodule showed negative for malignancy. Progressively rising CEA levels were noted over the following 5 years, but serial follow-up examinations did not find evidence of recurrence. Fluorodeoxyglucose-positron emission tomography/computed tomography (FDG-PET/CT) was performed subsequently and again showed focal FDG uptake in the right thyroid lobe. This time, FNAC revealed positive for malignancy, in favor of medullary thyroid carcinoma (MTC). The patient underwent total thyroidectomy and modified radical neck dissection, and MTC with cervical nodal metastasis (pT3N1) was diagnosed. He had cervical lymph nodes recurrence 2 years later, which was resected.

Conclusions

This case reminded us that FDG-PET/CT may detect occult tumors resulting in CEA elevation other than colorectal cancer. Moreover, FNA has a higher false negative rate in detecting MTC than other forms of thyroid cancer. Repeat FNAC for the initial negative cytology result and measure of serum calcitonin for the early MTC detection could be more helpful to avoid the delay in MTC diagnosis.

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Postoperative extracranial metastasis from glioblastoma: a case report and review of the literature

Abstract

Background

Glioblastoma is the most common primary malignant brain tumor. Extraneural metastases are rarely reported in the literature.

Case presentation

We report a case of a 38-year-old patient who was diagnosed with glioblastoma in 2015. Four months after surgery, local relapse was found and the patient received a second surgery. After another 4 months, we found a hard mass in the right posterior neck when she admitted to our department for fourth cycle of adjuvant chemotherapy. Immunohistochemical investigation supported the diagnosis of glioblastoma metastases to the neck after resection of the right neck mass. A few days later, spinal vertebral magnetic resonance imaging (MRI) confirmed multiple metastases in the thoracic, lumbar, sacral, and bilateral iliac bones.

Conclusions

Glioblastoma is the most common primary malignant brain tumor. Whole tumor resection and early radiotherapy and chemotherapy can delay recurrence and prolong survival. Extracranial metastases are extremely rare. We report this case with the aim of bringing attention to extracranial metastasis of brain glioma.

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Synergistic inhibition of tumor growth by combination treatment with drugs against different subpopulations of glioblastoma cells

Abstract

Background

Glioma stem cells (GSCs) contribute to tumor recurrence and drug resistance. This study characterizes the tumorigenesis of CD133⁺ cells and their sensitivity to pharmacological inhibition.

Methods

GSCs from human U87 and rat C6 glioblastoma cell lines were isolated via magnetic cell sorting using CD133 as a cancer stem cell marker. Cell proliferation was determined using the WST-1 assay. An intracranial mouse model and bioluminescence imaging were used to assess the effects of drugs on tumor growth in vivo.

Results

CD133⁺ cells expressed stem cell markers and exhibited self-renewal and enhanced tumor formation. Minocycline (Mino) was more effective in reducing the survival rate of CD133⁺ cells, whereas CD133⁻ cells were more sensitive to inhibition by the signal transducer and activator of transcription 3 (STAT3) inhibitor. Inhibition of STAT3 decreased the expression of CD133⁺ stem cell markers. The combination of Mino and STAT3 inhibitor synergistically reduced the cell viability of glioma cells. Furthermore, this combination synergistically suppressed tumor growth in nude mice.

Conclusion

The results suggest that concurrent targeting of different subpopulations of glioblastoma cells may be an effective therapeutic strategy for patients with malignant glioma.

http://ift.tt/2zJMgiI

Galectin 3 expression in primary oral squamous cell carcinomas

Abstract

Background

Immunologic factors can promote the progression of oral squamous cell carcinomas (oscc). The phylogenetic highly conserved protein Galectin 3 (Gal3) contributes to cell differentiation and immune homeostasis. There is evidence that Gal3 is involved in the progression of oscc and influences the regulation of macrophage polarization. Macrophage polarization (M1 vs. M2) in solid malignancies like oscc contributes to tumor immune-escape. However, the relationship between macrophage polarization and Gal3 expression in oscc is not yet understood. The current study analyzes the association between histomorphologic parameters (T-, N-, L- Pn-status, grading) and Gal3 expression resp. the ratio between Gal3 expressing cells and CD68 positive macrophages in oscc specimens.

Methods

Preoperative diagnostic biopsies (n = 26) and tumor resection specimens (n = 34) of T1/T2 oscc patients were immunohistochemically analyzed for Gal3 and CD68 expression. The number of Gal3 expressing cells and the ratio between CD68 and Gal3 expressing cells was quantitatively assessed.

Results

In biopsy and tumor resection specimens, the number of Gal3 positive cells as well as the Gal3/CD68 ratio were significantly (p < 0.05) higher in T2 oscc compared to T1 cases. In biopsy specimens, a significantly (p < 0.05) increased Gal3 expression and Gal3/CD68 ratio was associated with the progression marker lymph vessel infiltration (L1). Tumor resection specimens of cases with lymph node metastases (N+) had a significantly (p < 0.05) increased Gal3 expression. Additionally, a high Gal3/CD68 ratio correlated significantly (p < 0.05) with higher grading (G3) in tumor resection specimens.

Conclusion

High Gal3 expression in oscc is associated with tumor size (T-status) and parameters of malignancy (N-, L-status, grading). Gal3 might contribute to M2 macrophage mediated local immune tolerance. Gal3 expression shows association with prognosis in oscc and represent a potential therapeutic target.

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Clinicopathological factors influencing the outcomes of surgical treatment in patients with T4a hypopharyngeal cancer

Abstract

Background

The purpose of this study was to determine prognostic factors influencing outcomes of surgical treatment in patients with T4a hypopharyngeal cancer.

Methods

The present study enrolled 93 patients diagnosed with T4a hypopharyngeal cancer who underwent primary surgery between January 2005 and December 2015 at six medical centers in Korea. Primary tumor sites included pyriform sinus in 71 patients, posterior pharyngeal wall in 14 patients, and postcricoid region in 8 patients. Seventy-two patients received postoperative radio(chemo)therapy.

Results

Five-year disease-free survival (DFS) and disease-specific survival (DSS) rates were 38% and 45%, respectively. In univariate analysis, 5-year DFS was found to have significant and positive correlations with margin involvement (p < 0.001) and extracapsular spread (p = 0.025). Multivariate analysis confirmed that margin involvement (hazard ratio (HR): 2.81; 95% confidence interval (CI): 1.49-5.30; p = 0.001) and extracapsular spread (HR: 2.08; 95% CI: 1.08-3.99; p = 0.028) were significant factors associated with 5-year DFS. In univariate analysis, cervical lymph node metastasis (p = 0.048), lymphovascular invasion (p = 0.041), extracapsular spread (p = 0.015), and esophageal invasion (p = 0.033) were significant factors associated with 5-year DSS. In multivariate analysis, extracapsular spread (HR: 2.98; 95% CI: 1.39-6.42; p = 0.005) and esophageal invasion (HR: 2.87; 95% CI: 1.38-5.98; p = 0.005) remained significant factors associated with 5-year DSS.

Conclusion

Margin involvement and extracapsular spread are factors influencing recurrence while extracapsular spread and esophageal invasion are factors affecting survival in patients with T4a hypopharyngeal cancer treated by primary surgery.

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c-MYC drives a subset of high-risk pediatric neuroblastomas and is activated through mechanisms including enhancer hijacking and focal enhancer amplification [Research Articles]

The amplified MYCN gene serves as an oncogenic driver in approximately 20% of high-risk pediatric neuroblastomas. Here we show that the family member c-MYC is a potent transforming gene in a separate subset of high-risk neuroblastoma cases (~10%), based on (i) its upregulation by focal enhancer amplification or genomic rearrangements leading to enhancer hijacking, and (ii) its ability to transform neuroblastoma precursor cells in a transgenic animal model. The aberrant regulatory elements associated with oncogenic c-MYC activation include focally amplified distal enhancers and translocation of highly active enhancers from other genes to within topologically associating domains containing the c-MYC gene locus. The clinical outcome for patients with high levels of c-MYC expression is virtually identical to that of patients with amplification of the MYCN gene, a known high-risk feature of this disease. Together, these findings establish c-MYC as a bona fide oncogene in a clinically significant group of high-risk childhood neuroblastomas.

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Patterns of bone tracer uptake on SPECT-CT in symptomatic and asymptomatic patients with primary total hip arthroplasty

Abstract

Purpose

The primary purpose of this study was to compare bone tracer uptake (BTU) on SPECT/CT in symptomatic and asymptomatic total hip arthroplasty (THA) and identify a possible relationship between BTU patterns and patient's symptoms. The secondary purpose was to investigate if the fixation methods (cemented versus uncemented) lead to different BTU patterns.

Methods

A total of 58 THAs, 31 symptomatic (group S) and 27 asymptomatic (group AS), were prospectively collected and retrospectively analyzed. All symptomatic patients underwent standardized detailed history, clinical examination, radiographs and 99mTc-HDP SPECT/CT. BTU in SPECT/CT was quantified in three dimensions and anatomically localized in a scheme of quadrants and levels using a customized previously validated software. T tests were used on both quadrants and levels inside and between groups. A Pearson correlation was performed for BTU within the quadrants. An area under receiver operating characteristic curves was drawn in order to find a BTU value that could differentiate the two groups. Within the groups, patients with cemented and uncemented stems were compared for influences on BTU intensity.

Results

The causes of pain were identified in 61% of the patients. The most common problem was aseptic loosening (n = 12). In group AS, levels 1, 2 and 5 had similar BTUs. BTUs in these levels were significantly higher than in level 3, 4 and 6. In group S, no significant differences were seen in terms of BTU in level 1–5. However, BTU here was significantly higher than at level 6 (p < 0.001). In both groups, level 1, the superior, had a significantly higher BTU than level 2 (group AS p < 0.01, group S p < 0.05). Comparing the BTU of the two groups among levels, significant differences were found for level 4, level 5 and the entire stem areas (p < 0.05). The ROC curve calculated on the whole stem allowed identification of a BTU ratio of 3.1 that separated the 92.6% patients of group AS with BTU < 3.1 from the 54.8% of patients of group S with a BTU ≥ 3.1. With regards to the fixation technique, only the BTU at the level 6 in group S presented a significant difference between cemented and uncemented stems (p < 0.05).

Conclusions

Higher BTU levels significantly correlated with symptoms, but a normal BTU could not exclude a specific pathology after THA. A threshold of BTU in SPECT/CT was identified to distinguish between symptomatic and asymptomatic patients after THA.

http://ift.tt/2DpVUJQ

Correction to: 18F-NaF PET/CT: EANM procedure guidelines for bone imaging

Abstract

The original version of this article unfortunately contained an error. The name and affiliation of "Frédéric Paycha" needs to be corrected. Given in this article is the correct author name and affiliation.

http://ift.tt/2Ce0FGX

Validation of the mIBG skeletal SIOPEN scoring method in two independent high-risk neuroblastoma populations: the SIOPEN/HR-NBL1 and COG-A3973 trials

Abstract

Background

Validation of the prognostic value of the SIOPEN mIBG skeletal scoring system in two independent stage 4, mIBG avid, high-risk neuroblastoma populations.

Results

The semi-quantitative SIOPEN score evaluates skeletal meta-iodobenzylguanidine (mIBG) uptake on a 0–6 scale in 12 anatomical regions. Evaluable mIBG scans from 216 COG-A3973 and 341 SIOPEN/HR-NBL1 trial patients were reviewed pre- and post-induction chemotherapy. The prognostic value of skeletal scores for 5-year event free survival (5 yr.-EFS) was tested in the source and validation cohorts. At diagnosis, both cohorts showed a gradual non-linear increase in risk with cumulative scores. Several approaches were explored to test the relationship between score and EFS. Ultimately, a cutoff score of ≤3 was the most useful predictor across trials. A SIOPEN score ≤ 3 pre-induction was found in 15% SIOPEN patients and in 22% of COG patients and increased post-induction to 60% in SIOPEN patients and to 73% in COG patients. Baseline 5 yr.-EFS rates in the SIOPEN/HR-NBL1 cohort for scores ≤3 were 47% ± 7% versus 26% ± 3% for higher scores at diagnosis (p < 0.007) and 36% ± 4% versus 14% ± 4% (p < 0.001) for scores obtained post-induction. The COG-A3973 showed 5 yr.-EFS rates for scores ≤3 of 51% ± 7% versus 34% ± 4% for higher scores (p < 0.001) at diagnosis and 43% ± 5% versus 16% ± 6% (p = 0.004) for post-induction scores. Hazard ratios (HR) significantly favoured patients with scores ≤3 after adjustment for age and MYCN-amplification. Optimal outcomes were recorded in patients who achieved complete skeletal response.

Conclusions

Validation in two independent cohorts confirms the prognostic value of the SIOPEN skeletal score. In particular, patients with an absolute SIOPEN score > 3 after induction have very poor outcomes and should be considered for alternative therapeutic strategies.

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Correction to: Peptide receptor radionuclide therapy (PRRT) in European Neuroendocrine Tumour Society (ENETS) grade 3 (G3) neuroendocrine neoplasia (NEN) - a single-institution retrospective analysis

Abstract

On page 4 of the original version of this article, the text "Eight (29%) of the patients had significant FDG-avid disease (i.e. with intensity above liver parenchyma) prior to treatment" needs to be corrected.

http://ift.tt/2CeYaE1

Quantitative 18 F-DOPA PET/CT in pheochromocytoma: the relationship between tumor secretion and its biochemical phenotype

Abstract

Introduction

¹⁸F-FDOPA illustrates the properties of uptake and storage of catecholamines in pheochromocytomas (PHEOs). Until now, the relationship between ¹⁸F-FDOPA quantitative parameters and a PHEO secretory profile has not been specifically evaluated.

Materials and methods

Fifty-six patients (56% females, median age: 47.5 yrs) with non-metastatic PHEO, evaluated by ¹⁸F-FDOPA PET/CT, were included in this retrospective study. Forty-five patients had negative genetic testing (80.4%); five patients (8.9%) had RET, two patients (3.6%) had SDHB, two had SDHD (3.6%), one patient (1.8%) had NF1, and one patient had a VHL (1.8%) mutation. Correlation between ¹⁸F-FDOPA metabolic parameters (tumor SUVmax, tumor SUVmean, tumor SUVmax/liver SUVmax, MTV 42%, total lesion uptake), urinary metanephrines (MNs), and plasma chromogranin A (CgA) were evaluated.

Results

All patients had positive ¹⁸F-FDOPA PET/CT. On univariate analysis, there was a strong correlation between all metabolic parameters and urinary MNs and plasma chromogranin A (CgA). The highest correlations were observed between total lesion (TL) uptake and the value of urinary MNs regardless of their nature (p = 8.10⁻¹⁵ and r = 0.80) and between MTV 42% and plasma CgA levels (p = 2.10⁻⁹, r = 0.74). On multivariate analysis, the correlation of uptake parameters and CgA levels did not persist further due to the relation of CgA and tumor diameter. A correlation between TL uptake and the normetanephrine/metanephrine ratio (NMN/MN) was also found, a finding that was in accordance with in vitro studies, which were found to have a higher catecholamine content in epinephrine producing PHEOs.

Conclusion

This retrospective study shows a correlation between ¹⁸F-FDOPA uptake, especially using TL uptake, urinary MNs, and a PHEO biochemical phenotype. This illustrates that beyond its localization value, ¹⁸F-FDOPA PET further enables PHEO characterization at a specific metabolic level.

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Repeatability of tumour hypoxia imaging using [ 18 F]EF5 PET/CT in head and neck cancer

Abstract

Purpose

Hypoxia contributes to radiotherapy resistance and more aggressive behaviour of several types of cancer. This study was designed to evaluate the repeatability of intratumour uptake of the hypoxia tracer [¹⁸F]EF5 in paired PET/CT scans.

Methods

Ten patients with newly diagnosed head and neck cancer (HNC) received three static PET/CT scans before chemoradiotherapy: two with [¹⁸F]EF5 a median of 7 days apart and one with [¹⁸F]FDG. Metabolically active primary tumour volumes were defined in [¹⁸F]FDG images and transferred to co-registered [¹⁸F]EF5 images for repeatability analysis. A tumour-to-muscle uptake ratio (TMR) of 1.5 at 3 h from injection of [¹⁸F]EF5 was used as a threshold representing hypoxic tissue.

Results

In 10 paired [¹⁸F]EF5 PET/CT image sets, SUVmean, SUVmax, and TMR showed a good correlation with the intraclass correlation coefficients of 0.81, 0.85, and 0.87, respectively. The relative coefficients of repeatability for these parameters were 15%, 17%, and 10%, respectively. Fractional hypoxic volumes of the tumours in the repeated scans had a high correlation using the Spearman rank correlation test (r = 0.94). In a voxel-by-voxel TMR analysis between the repeated scans, the mean of Pearson correlation coefficients of individual patients was 0.65. The mean (± SD) difference of TMR in the pooled data set was 0.03 ± 0.20.

Conclusion

Pretreatment [¹⁸F]EF5 PET/CT within one week shows high repeatability and is feasible for the guiding of hypoxia-targeted treatment interventions in HNC.

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Klaus Bohndorf, Mark Anderson, Mark Davies, Herwig Imhof, Klaus Woertler: Imaging of bones and joints. A concise, multimodality approach

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Invited editorial for the paper by Silvoniemi et al. “Repeatability of tumor hypoxia imaging using [ 18 F]EF5 PET/CT in head and neck cancer.” in this issue of EJNMMI

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All that glitters is not gold - new reconstruction methods using Deauville criteria for patient reporting

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Added value of dedicated axillary hybrid 18F-FDG PET/MRI for improved axillary nodal staging in clinically node-positive breast cancer patients: a feasibility study

Abstract

Purpose

To investigate the feasibility and potential added value of dedicated axillary 18F-FDG hybrid PET/MRI, compared to standard imaging modalities (i.e. ultrasound [US], MRI and PET/CT), for axillary nodal staging in clinically node-positive breast cancer.

Methods

Twelve patients with clinically node-positive breast cancer underwent axillary US and dedicated axillary hybrid 18F-FDG PET/MRI. Nine of the 12 patients also underwent whole-body PET/CT. Maximum standardized uptake values (SUVmax) were measured for the primary breast tumor and the most FDG-avid axillary lymph node. A positive axillary lymph node on dedicated axillary hybrid PET/MRI was defined as a moderate to very intense FDG-avid lymph node. The diagnostic performance of dedicated axillary hybrid PET/MRI was calculated by comparing quantitative and its qualitative measurements to results of axillary US, MRI and PET/CT. The number of suspicious axillary lymph nodes was subdivided as follows: N0 (0 nodes), N1 (1–3 nodes), N2 (4–9 nodes) and N3 (≥ 10 nodes).

Results

According to dedicated axillary hybrid PET/MRI findings, seven patients were diagnosed with N1, four with N2 and one with N3. With regard to mean SUVmax, there was no significant difference in the primary tumor (9.0 [±5.0] vs. 8.6 [±5.7], p = 0.678) or the most FDG-avid axillary lymph node (7.8 [±5.3] vs. 7.7 [±4.3], p = 0.767) between dedicated axillary PET/MRI and PET/CT. Compared to standard imaging modalities, dedicated axillary hybrid PET/MRI resulted in changes in nodal status as follows: 40% compared to US, 75% compared to T2-weighted MRI, 40% compared to contrast-enhanced MRI, and 22% compared to PET/CT.

Conclusions

Adding dedicated axillary 18F-FDG hybrid PET/MRI to diagnostic work-up may improve the diagnostic performance of axillary nodal staging in clinically node-positive breast cancer patients.

http://ift.tt/2CenEBz

Delayed response after repeated 177 Lu-PSMA-617 radioligand therapy in patients with metastatic castration resistant prostate cancer

Abstract

Purpose

Radioligand therapy (RLT) using Lutetium-177 labeled PSMA-617 (Lu-PSMA) ligand is a new therapeutic option for salvage therapy in heavily pretreated patients with metastatic castration resistant prostate cancer. The aim of this retrospective study was to analyze response in patients receiving 3 cycles of Lu-PSMA.

Methods

Seventy-one patients (median age: 72 years; range 44–87) received 3 cycles of RLT with Lu-PSMA (mean administered activity: 6.016 ± 0.543 GBq) every 8 weeks. Response was evaluated using serum PSA levels and a PSA decline ≥50% was considered as biochemical response. Additionally, any PSA decline after the first cycle was evaluated for further therapy effects after the second and third cycle.

Results

A total of 213 cycles were performed in 71 patients. Data for response and adverse events were available for all patients. A PSA decline ≥50% and some PSA decline occurred in 56% and 66% of the patients. Of 30 patients with a PSA response after the first cycle, 28 remained responders and 12/41 of non-responders responded to further therapy cycles.

Conclusion

RLT with Lu-177-PSMA-617 shows respectable response rates. In this retrospective analysis, a relevant number of patients showed a delayed response, even if they did not respond to the first cycle of the therapy.

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The role of interim FDG PET-CT after induction chemotherapy as a predictor of concurrent chemoradiotherapy efficacy and prognosis for head and neck cancer

Abstract

Purpose

Induction chemotherapy (ICT) with docetaxel, cisplatin, and 5-fluorouracil (TPF) followed by concurrent chemoradiotherapy (CCRT) has the advantages of organ preservation and systemic control in head and neck cancer (HNC). Early prediction of CCRT efficacy may help identify patients who will benefit more from surgery than from CCRT. We investigated the role of interim 18-fluoro-2-deoxy-glucose positron emission tomography computed tomography (FDG PET-CT) after ICT to predict the efficacy of CCRT and clinical outcomes.

Methods

Tumor responses were retrospectively reviewed after CCRT based on the Response Evaluation Criteria in Solid Tumors. FDG PET-CT imaging was performed before and after three cycles of TPF. We examined the associations between the metabolic response (percentage decrease in the maximum standardized uptake value [SUVmax] and total metabolic tumor volume [MTV]) after ICT and complete response (CR) to CCRT, progression-free survival (PFS), and overall survival (OS).

Results

We studied 43 HNC patients with a median follow-up of 32.7 months. Lymph node (LN) SUVmax and total MTV decreases from baseline after ICT were greater in patients with a CR to CCRT than in non-CR patients (LN SUVmax, 88.8% vs. 62.5%, respectively; total MTV, 99.7% vs. 89.9%, respectively). Decreases in total MTV ≥ 78% and LN SUVmax ≥73% after ICT predicted CR to CCRT and longer OS and PFS.

Conclusions

Using interim FDG PET-CT to measure SUVmax and total MTV after three cycles of ICT may be a useful technique for identifying HNC patients who will benefit from CCRT and predicting survival outcomes.

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A score combining baseline neutrophilia and primary tumor SUV peak measured from FDG PET is associated with outcome in locally advanced cervical cancer

Abstract

Purpose

We investigated whether a score combining baseline neutrophilia and a PET biomarker could predict outcome in patients with locally advanced cervical cancer (LACC).

Methods

Patients homogeneously treated with definitive chemoradiation plus image-guided adaptive brachytherapy (IGABT) between 2006 and 2013 were analyzed retrospectively. We divided patients into two groups depending on the PET device used: a training set (TS) and a validation set (VS). Primary tumors were semi-automatically delineated on PET images, and 11 radiomics features were calculated (LIFEx software). A PET radiomic index was selected using the time-dependent area under the curve (td-AUC) for 3-year local control (LC). We defined the neutrophil SUV grade (NSG = 0, 1 or 2) score as the number of risk factors among (i) neutrophilia (neutrophil count >7 G/L) and (ii) high risk defined from the PET radiomic index. The NSG prognostic value was evaluated for LC and overall survival (OS).

Results

Data from 108 patients were analyzed. Estimated 3-year LC was 72% in the TS (n = 69) and 65% in the VS (n = 39). In the TS, SUV_peak was selected as the most LC-predictive biomarker (td-AUC = 0.75), and was independent from neutrophilia (p = 0.119). Neutrophilia (HR = 2.6), high-risk SUV_peak (SUV_peak > 10, HR = 4.4) and NSG = 2 (HR = 9.2) were associated with low probability of LC in TS. In multivariate analysis, NSG = 2 was independently associated with low probability of LC (HR = 7.5, p < 0.001) and OS (HR = 5.8, p = 0.001) in the TS. Results obtained in the VS (HR = 5.2 for OS and 3.5 for LC, p < 0.02) were promising.

Conclusion

This innovative scoring approach combining baseline neutrophilia and a PET biomarker provides an independent prognostic factor to consider for further clinical investigations.

http://ift.tt/2DohWfJ

Could 68 Ga-somatostatin analogues be an important alternative to 18 F-DOPA PET/CT in pediatrics?

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68 Ga-PSMA 11 ligand PET imaging in patients with biochemical recurrence after radical prostatectomy – diagnostic performance and impact on therapeutic decision-making

Abstract

Objective

To evaluate the diagnostic performance of [⁶⁸Ga]Ga-PSMA^HBED-CC conjugate 11 positron emission tomography (PSMA-PET) in the early detection of metastases in patients with biochemical recurrence (BCR) after radical prostatectomy (RP) for clinically non-metastatic prostate cancer, to compare it to CT/MRI alone and to assess its impact on further therapeutic decisions.

Material and methods

We retrospectively assessed 117 consecutive hormone-naïve BCR patients who had ⁶⁸Ga-PSMA 11 PET/CT (n = 46) or PET/MRI (n = 71) between May 2014 and January 2017. BCR was defined as two PSA rises above 0.2 ng/ml. Two dedicated uro-oncological imaging experts (radiology/nuclear medicine) reviewed separately all images. All results were presented in a blinded sequential fashion to a multidisciplinary tumorboard in order to assess the influence of PSMA-PET imaging on decision-making.

Results

The median time from RP to BCR was 36 months (IQR 16–72). Overall, 69 (59%) patients received postoperative radiotherapy. Median PSA level at the time of imaging was 1.04 ng/ml (IQR 0.58–1.87). PSMA-positive lesions were detected in 100 (85.5%) patients. Detection rates were 65% for a PSA value of 0.2 to <0.5 ng/ml, 85.7% for 0.5 to <1, 85.7% for 1 to <2 and 100% for ≥2. PSMA-positive lesions could be confirmed by either histology (16%), PSA decrease in metastasis-directed radiotherapy (45%) or additional information in diffusion-weighted imaging when PET/MRI was performed (18%) in 79% of patients. PSMA-PET detected lesions in 67 patients (57.3%) who had no suspicious correlates according to the RECIST 1.1 criteria on MRI or CT. PSMA-PET changed therapeutic decisions in 74.6% of these 67 patients (p < 0.001), with 86% of them being considered for metastases-directed therapies.

Conclusions

We confirm the high performance of PSMA-PET imaging for the detection of disease recurrence sites in patients with BCR after RP, even at relatively low PSA levels. Moreover, it adds significant information to standard CT/MRI, changing treatment strategies in a significant number of patients.

http://ift.tt/2DpOqXb

Texture analysis of high-resolution dedicated breast 18 F -FDG PET images correlates with immunohistochemical factors and subtype of breast cancer

Abstract

Purpose

This study aims to determine whether PET textural features measured with a new dedicated breast PET scanner reflect biological characteristics of breast tumors.

Methods

One hundred and thirty-nine breast tumors from 127 consecutive patients were included in this analysis. All of them underwent a ¹⁸F-FDG PET scan before treatment. Well-known PET quantitative parameters such as SUV _{m a x} , SUV _{m e a n} , metabolically active tumor volume (MATV) and total lesion glycolysis (TLG) were extracted. Together with these parameters, local, regional, and global heterogeneity descriptors, which included five textural features (TF), were computed. Immunohistochemical classification of breast cancer considered five subtypes: luminal A like (LA), luminal B like/HER2 − (LB −), luminal B like/HER2+ (LB+), HER2-positive-non-luminal (HER2pnl), and triple negative (TN). Associations between PET features and tumor characteristics were assessed using non-parametric hypothesis tests.

Results

Along with well-established associations, new correlations were found. HER2-positive tumors had significantly higher uptake (p < 0.001, AUCs > 0.70) and presented different global and regional heterogeneity (p = 0.002, p = 0.016, respectively, AUCs < 0.70). Nine out of ten analyzed features were significantly associated with immunohistochemical subtype. Uptake was lower for LA tumors (p < 0.001) with AUCs ranging from 0.71 to 0.88 for each subgroup comparison. Heterogeneity metrics were significantly associated when comparing LA and LB − (p < 0.01), being regional heterogeneity metrics more discriminative than any other parameter (AUC = 0.80 compared to AUC = 0.71 for SUV). LB+ and HER2pnl tumors also showed more regional heterogeneity than LA tumors (AUCs = 0.79 and 0.84, respectively). After comparison with whole-body PET studies, we observed an overall improvement in the classification ability of both non-heterogeneity metrics and textural features.

Conclusions

PET parameters extracted from high-resolution dedicated breast PET images showed new and stronger correlations with immunohistochemical factors and immunohistochemical subtype of breast cancer compared to whole-body PET.

http://ift.tt/2CfVVAx

Abstracts Presented at the Australian and New Zealand Association of Clinical Anatomists (ANZACA) 13th Annual Meeting “Artful Anatomy” 7th–9th December 2016, Australian National University (ANU) Medical School, Canberra, Australian Capital Territory, Australia

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Familial and Somatic BAP1 Mutations Inactivate ASXL1/2-Mediated Allosteric Regulation of BAP1 Deubiquitinase by Targeting Multiple Independent Domains

Deleterious mutations of the ubiquitin carboxy-terminal hydrolase BAP1 found in cancers are predicted to encode inactive truncated proteins, suggesting that loss of enzyme function is a primary tumorigenic mechanism. However, many tumors exhibit missense mutations or in-frame deletions or insertions, often outside the functionally critical UCH domain in this tumor suppressor protein. Thus, precisely how these mutations inactivate BAP1 is unknown. Here, we show how these mutations affect BAP1 interactions with the Polycomb group-like protein ASXL2, using combinations of computational modeling technology, molecular biology, and in vitro reconstitution biochemistry. We found that the BAP1-ASXL2 interaction is direct and high affinity, occurring through the ASXH domain of ASXL2, an obligate partner for BAP1 enzymatic activity. The ASXH domain was the minimal domain for binding the BAP1 ULD domain, and mutations on the surfaces of predicted helices of ASXH abolished BAP1 association and stimulation of BAP1 enzymatic activity. The BAP1-UCH, BAP1-ULD, and ASXH domains formed a cooperative stable ternary complex required for deubiquitination. We defined four classes of alterations in BAP1 outside the UCH domain, each failing to productively recruit ASXH to the wild-type BAP1 catalytic site via the ULD, resulting in loss of BAP1 ubiquitin hydrolase activity. Our results indicate that many BAP1 mutations act allosterically to inhibit ASXH binding, thereby leading to loss of enzyme activity. Small molecule approaches to reactivate latent wild-type UCH activity of these mutants might be therapeutically viable.

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Tumor treating fields (TTFields) delay DNA damage repair following radiation treatment of glioma cells

Abstract

Background

Tumor Treating Fields (TTFields) are an anti-neoplastic treatment modality delivered via application of alternating electric fields using insulated transducer arrays placed directly on the skin in the region surrounding the tumor. A Phase 3 clinical trial has demonstrated the effectiveness of continuous TTFields application in patients with glioblastoma during maintenance treatment with Temozolomide. The goal of this study was to evaluate the efficacy of combining TTFields with radiation treatment (RT) in glioma cells. We also examined the effect of TTFields transducer arrays on RT distribution in a phantom model and the impact on rat skin toxicity.

Methods

The efficacy of TTFields application after induction of DNA damage by RT or bleomycin was tested in U-118 MG and LN-18 glioma cells. The alkaline comet assay was used to measure repair of DNA lesions. Repair of DNA double strand breaks (DSBs) were assessed by analyzing γH2AX or Rad51 foci. DNA damage and repair signaled by the activation pattern of phospho-ATM (pS1981) and phospho-DNA-PKcs (pS2056) was evaluated by immunoblotting. The absorption of the RT energy by transducer arrays was measured by applying RT through arrays placed on a solid-state phantom. Skin toxicities were tested in rats irradiated daily through the arrays with 2Gy (total dose of 20Gy).

Results

TTFields synergistically enhanced the efficacy of RT in glioma cells. Application of TTFields to irradiated cells impaired repair of irradiation- or chemically-induced DNA damage, possibly by blocking homologous recombination repair. Transducer arrays presence caused a minor reduction in RT intensity at 20 mm and 60 mm below the arrays, but led to a significant increase in RT dosage at the phantom surface jeopardizing the "skin sparing effect". Nevertheless, transducer arrays placed on the rat skin during RT did not lead to additional skin reactions.

Conclusions

Administration of TTFields after RT increases glioma cells treatment efficacy possibly by inhibition of DNA damage repair. These preclinical results support the application of TTFields therapy immediately after RT as a viable regimen to enhance RT outcome. Phantom measurements and animal models imply that it may be possible to leave the transducer arrays in place during RT without increasing skin toxicities.

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Editorial Board

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Development and Validation of an ICD-10-Based Disability Predictive Index for Patients Admitted to Hospitals with Trauma

Publication date: Available online 28 December 2017
Source:Injury
Author(s): Tomoki Wada, Hideo Yasunaga, Hayato Yamana, Hiroki Matsui, Kiyohide Fushimi, Naoto Morimura
BackgroundThere was no established disability predictive measurement for patients with trauma that could be used in administrative claims databases. The aim of the present study was to develop and validate a diagnosis-based disability predictive index for severe physical disability at discharge using the International Classification of Diseases, 10th revision (ICD-10) coding.MethodsThis retrospective observational study used the Diagnosis Procedure Combination database in Japan. Patients who were admitted to hospitals with trauma and discharged alive from 01 April 2010 to 31 March 2015 were included. Pediatric patients under 15 years old were excluded. Data for patients admitted to hospitals from 01 April 2010 to 31 March 2013 was used for development of a disability predictive index (derivation cohort), while data for patients admitted to hospitals from 01 April 2013 to 31 March 2015 was used for the internal validation (validation cohort). The outcome of interest was severe physical disability defined as the Barthel Index score of <60 at discharge. Trauma-related ICD-10 codes were categorized into 36 injury groups with reference to the categorization used in the Global Burden of Diseases study 2013. A multivariable logistic regression analysis was performed for the outcome using the injury groups and patient baseline characteristics including patient age, sex, and Charlson Comorbidity Index (CCI) score in the derivation cohort. A score corresponding to a regression coefficient was assigned to each injury group. The disability predictive index for each patient was defined as the sum of the scores. The predictive performance of the index was validated using the receiver operating characteristic curve analysis in the validation cohort.ResultsThe derivation cohort included 1,475,158 patients, while the validation cohort included 939,659 patients. Of the 939,659 patients, 235,382 (25.0%) were discharged with severe physical disability. The c-statistics of the disability predictive index was 0.795 (95% confidence interval [CI] 0.794–0.795), while that of a model using the disability predictive index and patient baseline characteristics was 0.856 (95% CI 0.855–0.857).ConclusionsSevere physical disability at discharge may be well predicted with patient age, sex, CCI score, and the diagnosis-based disability predictive index in patients admitted to hospitals with trauma.



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Pembrolizumab in Asia-Pacific patients with advanced head and neck squamous cell carcinoma: analyses from KEYNOTE-012

Abstract

KEYNOTE-012 was a phase Ib, multicohort study designed to investigate efficacy and safety of pembrolizumab in advanced solid tumors. Results from the subset of patients with recurrent/metastatic head and neck squamous cell carcinoma (HNSCC) from the Asia-Pacific region are reported. Patients with recurrent/metastatic HNSCC, measurable disease (Response Evaluation Criteria in Solid Tumors, version 1.1 [RECIST v1.1]), and Eastern Cooperative Oncology Group performance status (ECOG PS) 0-1 were eligible for enrollment in the HNSCC expansion cohort. Patients received pembrolizumab 200 mg every 3 weeks. Response was assessed every 8 weeks. Co-primary endpoints were safety and overall response rate (ORR; RECIST v1.1, central review). Secondary endpoints included overall survival (OS) and response duration (DOR). Patients enrolled at any of the five centers throughout the Asia-Pacific region were included in these analyses. Twenty-six patients with HNSCC from the Asia-Pacific region received pembrolizumab. Median age was 62 years; 65% had ECOG PS 1; 62% received ≥2 prior therapies for recurrent/metastatic disease. Sixteen (62%) patients experienced a treatment-related adverse event (AE) of any grade, including 2 (8%) patients who experienced ≥1 events of grade 3 severity. No treatment-related deaths occurred. ORR was 19% (95% confidence interval [CI], 7–39). After a median follow-up of 12 months (range, 2–21), median DOR was not reached (range, 6–17+ months); four of five responses lasted ≥6 months. Median OS was 12 months (95% CI, 5–17). Pembrolizumab was well tolerated and had durable antitumor activity in patients with HNSCC from the Asia-Pacific region

This article is protected by copyright. All rights reserved.

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Bone marrow mesenchymal stem cells promote head and neck cancer progression through Periostin mediated PI3K/AKT/mTOR

Abstract

Bone marrow mesenchymal stem cells (BMMSCs) have been shown to be recruited to tumor microenvironment and exert a tumor-promoting effect in a variety of cancers. However, the molecular mechanisms related to the tumor-promoting effect of BMMSCs on head and neck cancer (HNC) were not clear. In this study, we investigated Periostin (POSTN) and its roles in tumor-promoting effect of BMMSCs on HNC. In vitro analysis of HNC cells cultured in BMMSCs conditioned media (MSC-CM) showed that MSC-CM significantly promoted the cancer progression by enhancing cell proliferation, migration, epithelial-mesenchymal transformation (EMT), altering expression of cell cycle regulatory proteins and inhibition of apoptosis. Moreover, MSC-CM promoted the expression of POSTN and POSTN promoted HNC progression through the activation of PI3K/AKT/mTOR signaling pathway. In a murine model of HNC, we found that BMMSCs promoted the tumor growth, invasion, metastasis and enhanced the expression of POSTN and EMT in tumor tissues. Clinical samples analysis further confirmed that the expression of POSTN and N-cadherin were correlated with pathological grade and lymph node metastasis of HNC. In conclusion, this study indicated that BMMSCs promoted proliferation, invasion, survival, tumorigenicity and migration of head and neck cancer through POSTN mediated PI3K/AKT/mTOR activation.

This article is protected by copyright. All rights reserved.

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Clinical Complications and Their Management

The hallmarks of thalassemias are ineffective erythropoiesis and peripheral hemolysis leading to a cascade of events responsible for several clinical complications. This pathophysiologic mechanism can be partially controlled by blood transfusions or by correction of the severity of ineffective erythropoiesis. Thalassemias include a spectrum of phenotypes. Two main groups can be clinically distinguished: transfusion-dependent (TDT) and non–transfusion-dependent (NTDT) thalassemia. Both conditions are characterized by several clinical complications along life; some are shared, whereas some have higher prevalence in one group over the other. The authors present the most common clinical complications in TDT and NTDT and their management.

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Accurate prognostic awareness facilitates, whereas better quality of life and more anxiety symptoms hinder end-of-life care discussions: a longitudinal survey study in terminally ill cancer patients’ last six months of life

Terminally ill cancer patients do not engage in end-of-life (EOL)-care discussions or do so only when death is imminent, despite guidelines for EOL-care discussions early in their disease trajectory. Most studies on patient-reported EOL-care discussions are cross-sectional without exploring the evolution of EOL-care discussions as death approaches. Cross-sectional studies cannot determine the direction of association between EOL-care discussions and patients' prognostic awareness, psychological well-being, and quality of life (QOL).

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Reply to “Prospective advances in fetal biomagnetometry - challenges remain”

Our recent simulation paper on fetal-maternal biomagnetic scanner (FM scanner) (Lew et al., 2017) demonstrated that it should be possible to develop a new type of instrument that can provide the online real-time information useful for advancing prenatal medicine on the electrophysiology of the maternal uterus and fetal heart and brain. Although the authors of the accompanying Letter to the Editor (Popescu and Gustafson, 2018), who have made significant contributions to the field of fetal monitoring, largely agree with this main point, they are not fully convinced that our FM scanner can detect the electrophysiological activity of the fetal brain in real time.

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Oxaliplatin and neuropathy: A role for sodium channels

Ensuring long-term quality of life in cancer survivors following treatment is critically important, particularly given the increasing effectiveness of treatments. Chemotherapy-induced peripheral neuropathy (CIPN) remains a major side effect of cancer therapy, with many commonly used chemotherapies, leading to early cessation and long-lasting disability (Park et al., 2013).

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Observations on muscle activity in REM sleep behavior disorder assessed with a semi-automated scoring algorithm

Rapid eye movement (REM) sleep behavior disorder (RBD) is a disorder defined by inappropriate muscle activity and enactment of dream content during REM sleep. RBD is closely connected with diseases pathologically characterized by abnormal aggregation of α-synuclein, including Parkinson's disease (PD), dementia with Lewy bodies and multiple system atrophy (St Louis et al., 2017). RBD often precedes overt motor symptoms of α-synucleinopathies by years (Postuma et al., 2015b; St Louis et al., 2017), providing a window to study their early pre-motor and prodromal disease stages.

http://ift.tt/2C63YDa