Transarterial radioembolization in patients with hepatocellular carcinoma of intermediate B2 substage

Abstract

Purpose

Patients with hepatocellular carcinoma (HCC) of intermediate stage (BCLC-B according to the Barcelona Clinic Liver Cancer classification) are a heterogeneous group with different degrees of liver function impairment and tumour burden. The recommended treatment is transarterial chemoembolization (TACE). However, patients in this group may be judged as poor candidates for TACE because the risk-benefit ratio is low. Such patients may receive transarterial radioembolization (TARE) only by entering a clinical trial. Experts have proposed that the stage could be further divided into four substages based on available evidence of treatment benefit. We report here, for the first time, the outcome in patients with BCLC-B2 substage HCC treated with TARE.

Methods

A retrospective analysis of the survival of 126 patients with BCLC-B2 substage HCC treated with TARE in three European hospitals was performed.

Results

Overall median survival in patients with BCLC-B2 substage was not significantly different in relation to tumour characteristics; 19.35 months (95% CI 8.27–30.42 months) in patients with a single large (>7 cm) HCC, and 18.43 months (95% CI 15.08–21.77 months) in patients with multinodular HCC (p = 0.27). However, there was a higher proportion of long-term survivors at 36 months among those with a single large tumour (29%) than among those with multiple tumours (16.8%).

Conclusion

Given the poor efficacy of TACE in treating patients with BCLC-B2 substage HCC, TARE treatment could be a better choice, especially in those with a large tumour.

http://bit.ly/2MCfx6X

Comparison of 18 F-GE-180 and dynamic 18 F-FET PET in high grade glioma: a double-tracer pilot study

Abstract

Background

PET represents a valuable tool for glioma imaging. In addition to amino acid tracers such as ¹⁸F-FET, PET targeting the 18-kDa mitochondrial translocator-protein (TSPO) is of high interest for high-grade glioma (HGG) imaging due to its upregulation in HGG cells. ¹⁸F-GE-180, a novel TSPO ligand, has shown a high target-to-background contrast in HGG. Therefore, we intra-individually compared its uptake characteristics to dynamic ¹⁸F-FET PET and contrast-enhanced MRI in patients with HGG.

Methods

Twenty HGG patients (nine IDH-wildtype, 11 IDH-mutant) at initial diagnosis (n = 8) or recurrence (n = 12) were consecutively included and underwent ¹⁸F-GE-180 PET, dynamic ¹⁸F-FET PET, and MRI. The maximal tumour-to-background ratios (TBR_max) and biological tumour volumes (BTV) were evaluated in ¹⁸F-GE-180 and ¹⁸F-FET PET. Dynamic ¹⁸F-FET PET analysis included the evaluation of minimal time-to-peak (TTP_min). In MRI, the volume of contrast-enhancement was delineated (VOL_CE). Volumes were spatially correlated using the Sørensen–Dice coefficient.

Results

The median TBR_max tended to be higher in ¹⁸F-GE-180 PET compared to ¹⁸F-FET PET [4.58 (2.33–8.95) vs 3.89 (1.56–7.15); p = 0.062] in the overall group. In subgroup analyses, IDH-wildtype gliomas showed a significantly higher median TBR_max in ¹⁸F-GE-180 PET compared to ¹⁸F-FET PET [5.45 (2.56–8.95) vs 4.06 (1.56–4.48); p = 0.008]; by contrast, no significant difference was observed in IDH-mutant gliomas [3.97 (2.33–6.81) vs 3.79 (2.01–7.15) p = 1.000]. Only 5/20 cases showed higher TBR_max in ¹⁸F-FET PET compared to ¹⁸F-GE-180 PET, all of them being IDH-mutant gliomas. No parameter in ¹⁸F-GE-180 PET correlated with TTP_min (p > 0.05 each). There was a tendency towards higher median BTV_GE-180 [32.1 (0.4–236.0) ml] compared to BTV_FET [19.3 (0.7–150.2) ml; p = 0.062] with a moderate spatial overlap [median Sørensen–Dice coefficient 0.55 (0.07–0.85)]. In MRI, median VOL_CE [9.7 (0.1–72.5) ml] was significantly smaller than both BTV_FET and BTV_GE180 (p < 0.001 each), leading to a poor spatial correlation with BTV_GE-180 [0.29 (0.01–0.48)] and BTV_FET [0.38 (0.01–0.68)].

Conclusion

PET with ¹⁸F-GE-180 and ¹⁸F-FET provides differing imaging information in HGG dependent on the IDH-mutational status, with diverging spatial overlap and vast exceedance of contrast-enhancement in MRI. Combined PET imaging might reveal new insights regarding non-invasive characterization of tumour heterogeneity and might influence patients' management.

http://bit.ly/2sVhWR6

Christopher E. Comstock, Christiane Kuhl (Eds.): Abbreviated MRI of the Breast: A Practical Guide

http://bit.ly/2MCVQw2

Diagnostic performance of choline PET for detection of hyperfunctioning parathyroid glands in hyperparathyroidism: a systematic review and meta-analysis

Abstract

Purpose

Hyperparathyroidism (HPT) is a common endocrine disorder caused by hyperfunctioning parathyroid glands (HP). The correct detection and localization of HP is challenging but crucial, as it may guide surgical treatment, particularly in patients with primary HPT. There is a growing body of data regarding the role of radiolabelled choline positron emission tomography (PET) in this setting. Therefore, we performed a systematic review and meta-analysis of the diagnostic performance of this method in detecting HP in patients with HPT.

Methods

This systematic review and meta-analysis was carried out according to PRISMA guidelines. A comprehensive computer literature search of PubMed/MEDLINE, EMBASE and Cochrane Library databases for studies published through May 2018 was performed using the following search algorithm: (a) "choline" or "fluorocholine" or "F-choline" or "C-choline" or "FCH" or "CH" or "FECH" or "FMCH" and (b) "PET" or "positron emission tomography" and (c) "parathyroid" or "hyperparathyroidism". The diagnostic performance of radiolabelled choline PET was expressed as sensitivity and positive predictive value (PPV) on a per-patient and per-lesion basis and as detection rate (DR) on a per-patient basis, with pooled proportion and 95% confidence interval (95% CI) obtained using a random-effects model.

Results

Eighteen studies were included in the systematic review. Fourteen articles (517 patients) were selected for the meta-analysis. The meta-analysis provided the following results on a per-patient analysis analysis: sensitivity 95% (95% CI: 92–97%), PPV 97% (95% CI: 95–98%) and DR 91% (95% CI: 87–94%). On a per-lesion analysis, pooled sensitivity and PPV were 92% (95% CI: 88–96) and 92% (95% CI: 89–95%), respectively. No significant heterogeneity was found among the selected studies.

Conclusions

Radiolabelled choline PET demonstrated excellent diagnostic performance in detecting HP in patients with HPT. Large multicentre studies and cost-effectiveness analyses are needed to better define the role of this imaging method in this setting.

http://bit.ly/2sRLgIl

Regulation of human brown adipose tissue by adenosine and A 2A receptors – studies with [ 15 O]H 2 O and [ 11 C]TMSX PET/CT

Abstract

Purpose

Brown adipose tissue (BAT) has emerged as a potential target to combat obesity and diabetes, but novel strategies to activate BAT are needed. Adenosine and A_2A receptor (A2AR) agonism activate BAT in rodents, and endogenous adenosine is released locally in BAT as a by-product of noradrenaline, but physiological data from humans is lacking. The purpose of this pilot study was to investigate the effects of exogenous adenosine on human BAT perfusion, and to determine the density of A2ARs in human BAT in vivo for the first time, using PET/CT imaging.

Methods

Healthy, lean men (n = 10) participated in PET/CT imaging with two radioligands. Perfusion of BAT, white adipose tissue (WAT) and muscle was quantified with [¹⁵O]H₂O at baseline, during cold exposure and during intravenous administration of adenosine. A2AR density of the tissues was quantified with [¹¹C]TMSX at baseline and during cold exposure.

Results

Adenosine increased the perfusion of BAT even more than cold exposure (baseline 8.3 ± 4.5, cold 19.6 ± 9.3, adenosine 28.6 ± 7.9 ml/100 g/min, p < 0.01). Distribution volume of [¹¹C]TMSX in BAT was significantly lower during cold exposure compared to baseline. In cold, low [¹¹C]TMSX binding coincided with high concentrations of noradrenaline.

Conclusions

Adenosine administration caused a maximal perfusion effect in human supraclavicular BAT, indicating increased oxidative metabolism. Cold exposure increased noradrenaline concentrations and decreased the density of A2AR available for radioligand binding in BAT, suggesting augmented release of endogenous adenosine. Our results show that adenosine and A2AR are relevant for activation of human BAT, and A2AR provides a future target for enhancing BAT metabolism.

http://bit.ly/2MIabaA

Ectopic corticotropin-releasing hormone syndrome caused by pancreatic neuroendocrine tumor localized by 68 Ga-DOTATATE PET/CT

http://bit.ly/2sS3rxF

Highly favourable outcomes with peptide receptor radionuclide therapy (PRRT) for metastatic rectal neuroendocrine neoplasia (NEN)

Abstract

Purpose

Rectal neuroendocrine neoplasia (NEN) is more common than other NEN origins, but is less commonly metastatic. However, when present, distant disease carries a particularly poor prognosis. Evidence guiding optimal treatment of such patients is lacking. We assessed PRRT outcomes in patients with somatostatin receptor (SSTR) positive metastatic rectal NEN from two referral centres.

Methods

Patients treated with PRRT were retrospectively reviewed. Morphologic (RECIST 1.1), SSTR imaging responses and toxicity were assessed 3 months post-PRRT. Kaplan-Meier estimate was used to determine progression-free survival (PFS) and overall survival (OS) from start of PRRT.

Results

Twenty-seven consecutive patients (M = 20, age 31-81 years) were reviewed. The majority (70%) had ENETs grade 2 disease (19 patients), three had Grade 3, one Grade 1, and four not documented. Overall, 63% (10/16 patients with available FDG PET/CT) had FDG avid disease. Twenty-six patients were treated for disease progression. Most had ¹⁷⁷Lu-DOTA-octreotate with median cumulative activity of 30 GBq, median four cycles. 14 patients had radiosensitising chemotherapy (5FU or capecitabine). At 3 months post-PRRT, CT disease control rate (DCR) was 96%: partial response was observed in 70% (19/27) and stable disease in 26%. All but one had partial SSTR imaging response. The median PFS was 29 months. Ten patients died, with median overall survival 81 months with a median follow-up of 67 months. Seventeen patients had further treatments after initial PRRT (10 had further cycles of PRRT). Three patients had grade 3 lymphopenia, without significant renal toxicity, MDS or leukaemia.

Conclusion

Our results indicate high efficacy and morphologic responses with minimal toxicity and very encouraging survival from PRRT in patients with metastatic rectal NEN despite the adverse prognostic features of this cohort. Further prospective PRRT trials are warranted in this subgroup.

http://bit.ly/2MIa272

Treatment of aggressive recurrent meningiomas: spinning towards peptide receptor radionuclide therapy

http://bit.ly/2sOSPj2

Bombardieri E, Seregni E, Evangelista L, Chiesa C, Chiti A (Eds.) Clinical Applications of Nuclear Medicine Targeted Therapy. Springer International Publishing Switzerland 2018. ISBN 978-3-319-63067-0

http://bit.ly/2FW4cyj

Influence of lanreotide on uptake of 68 Ga-DOTATATE in patients with neuroendocrine tumours: a prospective intra-patient evaluation

Abstract

Introduction

Somatostatin receptor imaging with PET is the standard of care for patients with a neuroendocrine tumour (NET). Since therapy and imaging with somatostatin analogues utilize the same receptor, current guidelines recommend withdrawing long-acting somatostatin analogues for 3-4 weeks prior to somatostatin receptor PET imaging. The aim of this study is to prospectively assess the effect of lanreotide use on the uptake of ⁶⁸Ga-DOTATATE intra-individually 1 day prior to and 1 day post injection of lanreotide.

Methods

Thirty-four patients with metastatic and/or unresectable NET and currently on lanreotide therapy for at least 4 months were included in the study. A ⁶⁸Ga-DOTATATE PET/CT scan was performed on the day before and the day after lanreotide injection. In each patient ⁶⁸Ga-DOTATATE uptake (SUV_max, _mean, _peak) was assessed in both tumour lesions and normal tissue. All scans were assessed by two blinded nuclear medicine physicians for visual analysis. Paired T-tests were performed to determine the differences between the scans.

Results

Of the 34 patients included, 31 were available for analyses in which 190 tumour lesions were measured. Uptake of ⁶⁸Ga-DOTATATE in tumour lesions was increased significantly after lanreotide, but decreased significantly in the liver, spleen, and thyroid gland resulting in a higher tumour-to-liver ratio.

Conclusion

Lanreotide injection prior to ⁶⁸Ga-DOTATATE PET/CT does not result in decreased tumour uptake. In contrast, tumour uptake was increased, whereas the uptake in normal organs is decreased, leading to an increased tumour-to-liver ratio. However, these differences were small and not deemed clinically relevant. These results strongly suggest that discontinuation of lanreotide injections in the weeks prior to ⁶⁸Ga-DOTATATE PET examinations is unnecessary and does not compromise nuclear medicine imaging results.

http://bit.ly/2MI9VIE

Comprehensive anatomical and functional imaging in patients with type I neurofibromatosis using simultaneous FDG-PET/MRI

Abstract

Purpose

To demonstrate the clinical use of FDG-PET/MRI for monitoring enlargement and metabolism of plexiform neurofibromas (PNF) in patients with neurofibromatosis type 1 (NF1), in whom the development of a malignant peripheral nerve sheath tumor (MPNST) is often a life limiting event.

Methods

NF1 patients who underwent a simultaneous FDG-PET/MRI examination in our institution from September 2012 to February 2018 were included. Indication was suspicion of malignant transformation of a PNF to MPNST. A maximum of six peripheral nerve lesions per patient were defined as targets. Standardized uptake values (SUV) and apparent diffusion coefficients (ADC) were measured. The presence of target sign and contrast-medium enhancement was visually recorded. Growth rates were estimated comparing prior or follow-up examinations and correlated with FDG uptake and ADC values. The presence of CNS lesions in cerebral T2 weighted images was recorded.

Results

In 28 NF1 patients a total number of 83 peripheral nerve tumors, 75 benign PNFs and eight MPNSTs, were selected as target lesions. The SUVs of MPNSTs were significantly higher than the SUVs of PNF (3.84 ± 3.98 [SUV_mean MPNSTs] vs. 1.85 ± 1.03 [SUV_mean PNF], P < .01). Similarly, lesion SUV_mean-to-liver SUV_mean ratios significantly differed between MPNSTs and PNF (3.20 ± 2.70 [MPNSTs] vs. 1.23 ± 0.61 [PNF]; P < .01). For differentiation between still benign PNF and MPNSTs, we defined SUV_max ≥ 2.78 as a significant cut-off value. Growth rate of PNF correlated significantly positively with SUV_mean (r_s = .41; P = .003). MRI parameters like ADC_mean (1.87 ± 0.24 × 10⁻³ mm²/s [PNF] vs. 1.76 ± 0.11 × 10⁻³ mm²/s [MPNSTs]; P > .05], contrast medium enhancement (P = .50) and target sign (P = .86) did not differ between groups.

Conclusion

Simultaneous FDG-PET/MRI is a comprehensive imaging modality for monitoring PNF in NF1 patients. The combined acquisition of both morphologic information in MRI and metabolic information in PET enables the correlation of lesion growth rates with metabolic activity and to define SUV thresholds of significance to identify malignant transformation, which is of utmost clinical significance.

http://bit.ly/2MFfMhA

FET PET reveals considerable spatial differences in tumour burden compared to conventional MRI in newly diagnosed glioblastoma

Abstract

Purpose

Areas of contrast enhancement (CE) on MRI are usually the target for resection or radiotherapy target volume definition in glioblastomas. However, the solid tumour mass may extend beyond areas of CE. Amino acid PET can detect parts of the tumour that show no CE. We systematically investigated tumour volumes delineated by amino acid PET and MRI in patients with newly diagnosed, untreated glioblastoma.

Methods

Preoperatively, 50 patients with neuropathologically confirmed glioblastoma underwent O-(2-[¹⁸F]-fluoroethyl)-l-tyrosine (FET) PET, and fluid-attenuated inversion recovery (FLAIR) and contrast-enhanced MRI. Areas of CE were manually segmented. FET PET tumour volumes were segmented using a tumour-to-brain ratio of ≥1.6. The percentage overlap volumes, and Dice and Jaccard spatial similarity coefficients (DSC, JSC) were calculated. FLAIR images were evaluated visually.

Results

In 43 patients (86%), the FET tumour volume was significantly larger than the CE volume (21.5 ± 14.3 mL vs. 9.4 ± 11.3 mL; P < 0.001). Forty patients (80%) showed both increased uptake of FET and CE. In these 40 patients, the spatial similarity between FET uptake and CE was low (mean DSC 0.39 ± 0.21, mean JSC 0.26 ± 0.16). Ten patients (20%) showed no CE, and one of these patients showed no FET uptake. In five patients (10%), increased FET uptake was present outside areas of FLAIR hyperintensity.

Conclusion

Our results show that the metabolically active tumour volume delineated by FET PET is significantly larger than tumour volume delineated by CE. Furthermore, the results strongly suggest that the information derived from both imaging modalities should be integrated into the management of patients with newly diagnosed glioblastoma.

http://bit.ly/2MI9RIU

Personalized 177 Lu-octreotate peptide receptor radionuclide therapy of neuroendocrine tumours: initial results from the P-PRRT trial

Abstract

Purpose

Peptide receptor radionuclide therapy (PRRT) is mostly administered using a fixed injected activity (IA) per cycle. This empiric regime results in highly variable absorbed doses to the critical organs and undertreatment of the majority of patients. We conceived a personalized PRRT protocol in which the IA is adjusted to deliver a prescribed absorbed dose to the kidney, with the aim to safely increase tumour irradiation. We herein report on the initial results of our prospective study of personalized PRRT, the P-PRRT Trial (NCT02754297).

Methods

PRRT-naïve patients with progressive and/or symptomatic neuroendocrine tumour (NET) were scheduled to receive a four-cycle induction course of ¹⁷⁷Lu-octreotate with quantitative SPECT/CT-based dosimetry. The IA was personalized according to the glomerular filtration rate and the body surface area for the first cycle, and according to the prior renal Gy/GBq for the subsequent cycles. The prescribed renal absorbed dose of 23 Gy was reduced by 25–50% in case of significant renal or haematological impairment. Responders were allowed to receive consolidation or maintenance cycles, for each of which 6 Gy to the kidney were prescribed. We simulated the empiric PRRT regime by fixing the IA at 7.4 GBq per cycle, with the same percentage reductions as above. Radiological, molecular imaging, biochemical, and quality of life responses, as well as safety, were assessed.

Results

Fifty-two patients underwent 171 cycles. In 34 patients who completed the induction course, a median cumulative IA of 36.1 (range, 6.3–78.6) GBq was administered, and the median cumulative kidney and maximum tumour absorbed doses were 22.1 (range, 8.3–24.3) Gy and 185.7 (range: 15.2–443.1) Gy respectively. Compared with the simulated fixed-IA induction regime, there was a median 1.26-fold increase (range, 0.47–2.12 fold) in the cumulative maximum tumour absorbed dose, which was higher in 85.3% of patients. In 39 assessable patients, the best objective response was partial response in nine (23.1%), minor response in 14 (35.9%), stable disease in 13 (33.3%) and progressive disease in three patients (7.7%). In particular, 11 of 13 patients (84.6%) with pancreatic NET had partial or minor response. The global health status/quality of life score significantly increased in 50% of patients. Acute and subacute side-effects were all of grade 1 or 2, and the most common were nausea (in 32.7% of patients) and fatigue (in 30.8% of patients) respectively. Subacute grade 3 or 4 toxicities occurred in less than 10% of patients, with the exception of lymphocytopenia in 51.9% of patients, without any clinical consequences however. No patient experienced severe renal toxicity.

Conclusions

Personalized PRRT makes it possible to safely increase tumour irradiation in the majority of patients. Our first results indicate a favourable tolerance profile, which appears similar to that of the empiric regime. The response rates are promising, in particular in patients with NET of pancreatic origin.

http://bit.ly/2sUMqD3

The EANM practical guidelines for sentinel lymph node localisation in oral cavity squamous cell carcinoma

Abstract

Purpose

Sentinel lymph node biopsy is an essential staging tool in patients with clinically localized oral cavity squamous cell carcinoma. The harvesting of a sentinel lymph node entails a sequence of procedures with participation of specialists in nuclear medicine, radiology, surgery, and pathology. The aim of this document is to provide guidelines for nuclear medicine physicians performing lymphoscintigraphy for sentinel lymph node detection in patients with early N0 oral cavity squamous cell carcinoma.

Methods

These practice guidelines were written and have been approved by the European Association of Nuclear Medicine (EANM) and the International Atomic Energy Agency (IAEA) to promote high-quality lymphoscintigraphy. The final result has been discussed by distinguished experts from the EANM Oncology Committee, and national nuclear medicine societies. The document has been endorsed by the Society of Nuclear Medicine and Molecular Imaging (SNMMI).

These guidelines, together with another two focused on Surgery and Pathology (and published in specialised journals), are part of the synergistic efforts developed in preparation for the "2018 Sentinel Node Biopsy in Head and Neck Consensus Conference".

Conclusion

The present practice guidelines will help nuclear medicine practitioners play their essential role in providing high-quality lymphatic mapping for the care of early N0 oral cavity squamous cell carcinoma patients.

http://bit.ly/2FTTLLz

Additional value of integrated 18 F-choline PET/4D contrast-enhanced CT in the localization of hyperfunctioning parathyroid glands and correlation with molecular profile

Abstract

Purpose

The localization of hyperfunctioning parathyroid gland(s) (HPTG) in patients with primary hyperparathyroidism (PHPT) with negative or inconclusive first-line imaging is a significant challenge. This study aimed to evaluate the role of integrated ¹⁸F-choline PET/4D contrast-enhanced computed tomography (4DCeCT) in these patients, compare its detection rate and sensitivity with those of ¹⁸F-choline PET/CT and (4DCeCT), and analyse the association between choline metabolism and morphological, biochemical and molecular parameters of HPTG.

Methods

We prospectively enrolled 44 PHPT patients with negative or inconclusive first-line imaging. ¹⁸F-Choline PET/CT and 4DCeCT were performed at the same time, and integrated ¹⁸F-choline PET/4DCeCT images were obtained after coregistration. Experienced physicians examined the images. The SUVratio and degree of contrast enhancement were recorded for each positive finding. Histopathology, laboratory and multidisciplinary follow-up were used as the standard of reference. Both the detection rates and sensitivities of the three imaging modalities were calculated retrospectively. Immunohistochemistry was performed to evaluate the molecular profile of HPTGs.

Results

¹⁸F-Choline PET/4DCeCT was positive in 32 of 44 patients with PHPT (detection rate 72.7%), and 31 of 31 surgically treated patients (sensitivity 100%). These results were significantly (p < 0.05) better than those of ¹⁸F-choline PET/CT (56.8% and 80%, respectively) and those of 4DCeCT (54.5 and 74%, respectively). A significant correlation between SUV and calcium level was found. In a multivariate analysis, only calcium level was significantly associated with ¹⁸F-choline PET/4DCeCT findings. SUVratio and Ki67 expression were significantly correlated.

Conclusion

Integrated ¹⁸F-choline PET/4DCeCT should be considered as an effective tool to detect PHPT in patients with negative or inconclusive first-line imaging. Choline metabolism is correlated with both calcium level and Ki67 expression in HPTG.

http://bit.ly/2sUMqmx

Yttrium-90 glass microspheres radioembolization (RE) for biliary tract cancer: a large single-center experience

Abstract

Purpose

Radioembolization (RE) is a promising treatment option for biliary tract cancers (BTC). We report here the largest series to date using this treatment modality.

Methods

We retrospectively studied data from 64 patients treated outside prospective clinical trial at our institution. We studied baseline characteristics as potential prognostic factors. We studied dose delivered to the tumor as predictive factors of outcomes in patients not receiving concomitant chemotherapy.

Results

The Progression-Free Survival and Overall Survival (OS) were 7.6 months [95% Confidence Interval (CI): 4.6–10.6] and 16.4 months [95% CI: 7.8–25.0] in the whole cohort. The factors independently associated with OS in multivariable analysis were the primary localization of ICC (HR = 0.27, 95% CI: 0.11–0.68, p = 0.005) and a PS > 0 (HR = 2.21, 95% CI: 1.11–4.38, p = 0.024). During follow-up, 12 patients (19%) underwent surgery following downstaging, with a median OS of 51.9 months. In patients not treated with concomitant chemotherapy (n = 31), OS was significantly higher in patients with a dose delivered to the tumor 260Gy or higher than in patients with a dose delivered to the tumor lower than 260Gy (median 28.2 vs 11.4 months, log-rank p = 0.019).

Conclusion

Our results confirm that RE is a promising treatment modality in BTC. A high proportion of patients could be downstaged to surgery, with promising long-term survival. Dose delivered to the tumor correlated with clinical outcomes when chemotherapy was not used concomitantly.

http://bit.ly/2FUloUL

The Dantastic Mr. Tox & Howard – S02E07 – Release the Kratom

Alternative treatments for opioid use disorder and music with Dr. Ed Boyer Join Dan (@drusyniak) &Howard (@heshiegreshie) as they speak with Dr. Ed Boyer about therapies for opioid use disorder, including kratom, ibogaine, and loperamide. Great stuff, deep science and a dispelling of some myths while recognizing some less than savvy science out there. . […]

EMCrit Project by Tox & Hound.

http://bit.ly/2SbY4HJ

Ethical Issues Across the IDEAL Stages of Surgical Innovation

No abstract available

http://bit.ly/2SJxqDb

Novel Anthraquinone Derivatives as Dual Inhibitors of Topoisomerase 2 and Casein Kinase 2: In Silico Studies, Synthesis and Biological Evaluation on Leukemic Cell Lines

Background: Cancer being a complex disease, single targeting agents remain unsuccessful. This calls for "multiple targeting", wherein a single drug is so designed that it will modulate the activity of multiple protein targets. Topoisomerase 2 (Top2) helps in removing DNA tangles and super-coiling during cellular replication, Casein Kinase 2 (CK2) is involved in the phosphorylation of a multitude of protein targets. Thus, in the present work, we have tried to develop dual inhibitors of Top2 and CK2.

Objective: With this view, in the present work, 2 human proteins, Top2 and CK2 have been targeted to achieve the anti-proliferative effects.

Methods: Novel 1-acetylamidoanthraquinone (3a-3y) derivatives were designed, synthesized and their structures were elucidated by analytical and spectral characterization techniques (FTIR, 1H NMR, 13C NMR and Mass Spectroscopy). The synthesized compounds were then subjected to evaluation of cytotoxic potential by the Sulforhodamine B (SRB) protein assay, using HL60 and K562 cell lines. Ten compounds were analyzed for Top2, CK2 enzyme inhibitory potential. Further, top three compounds were subjected to cell cycle analysis.

Results: The compounds 3a to 3c, 3e, 3f, 3i to 3p, 3t and 3x showed excellent cytotoxic activity to HL-60 cell line indicating their high anti-proliferative potential in AML. The compounds 3a to 3c, 3e, 3f, 3i to 3p and 3y have shown good to moderate activity on K-562 cell line. Compounds 3e, 3f, 3i, 3x and 3y were found more cytotoxic than standard doxorubicin. In cell cycle analysis, the cells (79-85%) were found to arrest in the G0/G1 phase.

Conclusion: We have successfully designed, synthesized, purified and structurally characterized 1- acetylamidoanthraquinone derivatives. Even though our compounds need design optimization to further increase enzyme inhibition, their overall anti-proliferative effects were found to be encouraging.

http://bit.ly/2Sehxrt

Comparison of intravenous, topical or combined routes of tranexamic acid administration in patients undergoing total knee and hip arthroplasty: a meta-analysis of randomised controlled trials

Objective

This study aimed to compare the effects of intravenous, topical and combined routes of tranexamic acid (TXA) administration on blood loss and transfusion requirements in patients undergoing total knee arthroplasty (TKA) and total hip arthroplasty (THA).

Design

This was a meta-analysis of randomised controlled trials (RCT) wherein the weighted mean difference (WMD) and relative risk (RR) were used for data synthesis applied in the random effects model. Stratified analyses based on the surgery type, region, intravenous and topical TXA dose and transfusion protocol were also conducted. The main outcomes included intraoperative and total blood loss volume, transfusion rate, low postoperative haemoglobin (Hb) level and postoperative Hb decline. However, the secondary outcomes included length of hospital stay (LOS) and/or occurrence of venous thromboembolism (VTE).

Setting

We searched the PubMed, Embase and Cochrane CENTRAL databases for RCTs that compared different routes of TXA administration.

Participants

Patients undergoing TKA or THA.

Interventions

Intravenous, topical or combined intravenous and topical TXA.

Results

Twenty-six RCTs were selected, and the intravenous route did not differ substantially from the topical route with respect to the total blood loss volume (WMD=30.92, p=0.31), drain blood loss (WMD=–34.53, p=0.50), postoperative Hb levels (WMD=–0.01, p=0.96), Hb decline (WMD=–0.39, p=0.08), LOS (WMD=0.15, p=0.38), transfusion rate (RR=1.08, p=0.75) and VTE occurrence (RR=1.89, p=0.15). Compared with the combined-delivery group, the single-route group had significantly increased total blood loss volume (WMD=198.07, p<0.05), greater Hb decline (WMD=0.56, p<0.05) and higher transfusion rates (RR=2.51, p<0.05). However, no significant difference was noted in the drain blood loss, postoperative Hb levels and VTE events between the two groups. The intravenous and topical routes had comparable efficacy and safety profiles.

Conclusions

The combination of intravenous and topical TXA was relatively more effective in controlling bleeding without increased risk of VTE.

http://bit.ly/2Wqnh0E

Prostate care and prostate cancer from the perspectives of undiagnosed men: a systematic review of qualitative research

Objectives

To summarise and evaluate evidence from men who had not been diagnosed with prostate cancer about their perspectives on prostate care and prostate cancer.

Design

A systematic review of qualitative research, on the perspectives of non-cancerous men regarding prostate cancer prevention and care.

Setting

A wide range of settings including primary and secondary care.

Participants

Men from varied demographic backgrounds ranging between 40 to 80 years of age.

Data sources

Three databases (Ovid MEDLINE, Informit, PsychInfo) and Google Scholar were searched for peer-reviewed papers in English reporting research using qualitative methods (in-depth or semistructured interviews and focus groups).

Review methods

Thematic analysis using inductive and deductive codes. Thematic synthesis was achieved through iterative open, axial and thematic coding.

Results

Eight papers (reporting seven studies conducted in Australia, UK and Germany) met inclusion criteria. Four major themes were identified: understanding prostate cancer, masculinity and prostate cancer, barriers to prostate healthcare and managing prostate health. It was reported that men often did not understand screening, prostate anatomy or their prostate cancer risk, and that concerns about masculinity could deter men from seeking health checks. There was evidence of a need to improve doctor–patient communication about case finding.

Conclusion

Further investigation is required to identify and understand any differences in the perspectives and experiences of men who have not been diagnosed with prostate cancer in metropolitan and regional areas, especially where there may be variations in access to healthcare

http://bit.ly/2RkElkF

Exploring obstetricians, midwives and general practitioners approach to weight management in pregnant women with a BMI >=25 kg/m2: a qualitative study

Objective

The aim of this study was to explore healthcare professionals' (HCPs) beliefs and attitudes towards weight management for pregnant women with a body mass index (BMI) ≥25 kg/m².

Design

Qualitative study.

Setting

A public antenatal clinic in a large academic maternity hospital in Cork, Ireland, and general practice clinics in the same region.

Participants

HCPs such as hospital-based midwives and consultant obstetricians and general practitioners (GPs).

Method

Semistructured interviews were conducted with a purposive sample of hospital-based HCPs and a sample of GPs working in the same region. Interviews were recorded, transcribed and thematically analysed using NVivo software.

Results

Seventeen HCPs were interviewed (hospital based=10; GPs=7). Four themes identified the complexity of weight management in pregnancy and the challenges HCPs faced when trying to balance the medical and psychosocial needs of the women. HCPs acknowledged weight as a sensitive conversation topic, leading to a 'softly-softly approach' to weight management. HCPs tried to strike a balance between being woman centred and empathetic and medicalising the conversation. HCPs described 'doing what you can with what you have' and shifting the focus to managing obstetric complications. Furthermore, there were unclear roles and responsibilities in terms of weight management.

Conclusion

HCPs need to have standardised approaches and evidence-based guidelines that support the consistent monitoring and management of weight during pregnancy.

http://bit.ly/2RrN2di

Acceptability, usability and utility of a personalised application in promoting behavioural change in patients with osteoarthritis: a feasibility study in Norway

Objective

The dynamic and interactive mobile application Vett was designed to help change behaviour and is based on cognitive, motivational and visual techniques. Our aim is to investigate the acceptability, usability and utility of Vett as a personalised application for goal achievement.

Setting

The trial took place at the rheumatology clinic at Diakonhjemmet Hospital, Oslo, Norway from January to June 2015.

Participants

Twelve participants with osteoarthritis were recruited from a 3.5-hour multidisciplinary group-based educational programme (osteoarthritis school).

Interventions

With the help of a physician, each participant followed a customised 12-week mixed-mode goal achievement plan with digital support based on preset goals, self-monitoring and individual feedback. Acceptability was measured as the perceived degree of goal achievement using a validated habit questionnaire scaled from 0 to 100. Utility and usability were assessed via 10 weekly questions and adherence by fulfilment of predetermined tasks.

Results

Mean goal achievement was 73 (95% CI 68 to 78), an increase of 22 (95% Cl 17 to 26, p<0.01), which equals 48% improvement (95% CI 32% to 59%). Mean user satisfaction was 81 (95% CI 76 to 85), and technical usability was 80 (95% CI 75 to 84), which both increased during the study period.

Conclusion

The high levels of acceptability, usability and utility support the feasibility of the personalised application Vett as a viable goal achievement tool.

http://bit.ly/2WtO5gf

Life satisfaction, job satisfaction, life orientation and occupational burnout among nurses and midwives in medical institutions in Poland: a cross-sectional study

Objectives

To assess life satisfaction, job satisfaction, life orientation and the level of professional burnout in a group of professionally active nurses and midwives.

Design

A cross-sectional study.

Setting

This study was conducted between March and October of 2017 during specialisation training at the European Centre for Postgraduate Education in Wroclaw, Poland.

Participants

A group of 350 professionally active nurses (n=293) and midwives (n=57) were enrolled in the study.

Outcome measures

Associations between burnout and selected life-related and job-related outcomes using (1) the Satisfaction With Job Scale, (2) the Satisfaction With Life Scale (SWLS), (3) the Life Orientation Test-Revised, (4) the Maslach Burnout Inventory and the Authors' Designed Questionnaire regarding sociodemographic factors. The level of statistical significance was set at p≤0.05 (with a CI of 95%).

Results

The vast majority of participants were those in the ages of 41–50 years old (40.57%), women (96.86%) and people with bachelor's degree (46.29%). The average overall rate for occupational burnout was 34.67 per 100 points. Assessment of occupational burnout subscale showed that the most significant factor was emotional exhaustion at 39.14 points (SD=28.15). Job satisfaction, life satisfaction and life orientation assessed with SWLS significantly affects each of the occupational burnout subscales (p<0.05).

Conclusions

The level of occupational burnout in nurses and midwives appeared to be low. It has been revealed that such determinants as life satisfaction, job satisfaction and life orientation do not allow for developing an occupational burnout.

http://bit.ly/2RkEch7

Financial performance of English NHS trusts and variation in clinical outcomes: a longitudinal observational study

Objectives

To examine the association between financial performance as measured by operating margin (surplus/deficit as a proportion of turnover) and clinical outcomes in English National Health Service (NHS) trusts.

Setting

Longitudinal, observational study in 149 acute NHS trusts in England between the financial years 2011 and 2016.

Participants

Our analysis focused on outcomes at individual NHS Trust-level (composed of one or more acute hospitals).

Primary and secondary outcomes

Outcome measures included readmissions, inpatient satisfaction score and the following process measures: emergency department (Accident and Emergency (A&E)) waiting time targets, cancer referral and treatment targets and delayed transfers of care (DTOCs).

Results

There was a progressive increase in the proportion of trusts in financial deficit: 22% in 2011, 27% in 2012, 28% in 2013, 51% in 2014, 68% in 2015 and 91% in 2016. In linear regression analyses, there was no significant association between operating margin and clinical outcomes (readmission rate or inpatient satisfaction score). There was, however, a significant association between operating margin and process measures (DTOCs, A&E breaches and cancer waiting time targets). Between the best and worst financially performing Trusts, there was an approximately 2-fold increase in A&E breaches and DTOCs overall although this variation decreased over the 6 years. Between the best and worst performing trusts on cancer targets, the magnitude of difference was smaller (1.16 and 1.15-fold), although the variation slowly rose during the 6 years.

Conclusions

Operating margins in English NHS trusts progressively worsened during 2011–2016, and this change was associated with poorer performance on several process measures but not with hospital readmissions or inpatient satisfaction. Significant variation exists between the best and worst financially performing Trusts. Further research is needed to examine the causal nature of relationships between financial performance, process measures and outcomes.

http://bit.ly/2WqmRY8

Bortezomib in antibody-mediated autoimmune diseases (TAVAB): study protocol for a unicentric, non-randomised, non-placebo controlled trial

Introduction

The clinical characteristics of autoantibody-mediated autoimmune diseases are diverse. Yet, medical treatment and the associated complications are similar, that is, the occurrence of long-term side effects and the problem that a significant proportion of patients are non-responders. Therefore, new therapeutic options are needed. Bortezomib, a proteasome inhibitor, is effective in the treatment of multiple myeloma and data from experimental models and case reports suggest an effect in the treatment of autoantibody-mediated autoimmunity. In our study, we will determine the effect of bortezomib treatment on a shared surrogate parameter for clinical efficacy, namely change in autoantibody levels, which we chose as primary parameter.

Methods and analysis

We designed a phase IIa trial with altogether n=18 treatment-refractory patients suffering from myasthenia gravis, systemic lupus erythematosus and rheumatoid arthritis that will be treated with bortezomib add-on to pre-existing therapy. Primary endpoint is the change in autoantibody levels 6 months after therapy. Secondary endpoints include concomitant medication, disease-specific clinical scores and measures of quality of life and activities of daily living.

Ethics and dissemination

Safety parameters include neurophysiological and clinical signs of peripheral neuropathy as well as potential central nervous system side effects determined by olfactory and neuropsychological testing. The study has been approved by the local ethical committee and first participants have already been enrolled. This proof of concept study will contribute to improve our understanding of plasma cell-specific treatment approaches by assessing its safety and efficacy in reducing serum levels of antibodies known to mediate autoimmune disorders.

We plan to publish the final results of our study in a peer reviewed journal and to present our findings at international conferences.

Trial registration number

NCT02102594.

http://bit.ly/2RnLCQO

Inhaler technique education in elderly patients with asthma or COPD: impact on disease exacerbations--a protocol for a single-blinded randomised controlled trial

Introduction

Chronic Obstructive Pulmonary Disease (COPD)and asthma affect more than 10% of the population. Most patients use their inhaler incorrectly, mainly the elderly, thereby becoming more susceptible to poor clinical control and exacerbations. Placebo device training is regarded as one of the best teaching methods, but there is scarce evidence to support it as the most effective one to improve major clinical outcomes. Our objective is to perform a single-blinded RCT to assess the impact of this education tool in these patients.

Methods and analysis

A multicentre single-blinded Randomised Controlled Trial (RCT) will be set up, comparing an inhaler education programme with a teach-to-goal placebo-device training versus usual care, with a 1-year follow-up, in patients above 65 years of age with asthma or COPD. Intervention will be provided at baseline, and after 3 and 6 months, with interim analysis at an intermediate time point. Exacerbation rates were set as primary outcomes, and quality of life, adherence rates, clinical control and respiratory function were chosen as secondary outcomes. A sample size of 146 participants (73 in each arm) was estimated as adequate to detect a 50% reduction in event rates. Two-sample proportions ² test will be used to study primary outcome and subgroup analysis will be carried out according to major baseline characteristics.

Ethics and dissemination

Every participant will sign a written consent form. A Data Safety Monitoring Board will be set up to evaluate data throughout the study and to monitor early stopping criteria. Identity of all participants will be protected. This protocol was approved on 22 November 2017 by the local Ethics Committee of University of Beira Interior, with the reference number CE-UBI-Pj-2017–025. Results will be presented in scientific meetings and published in peer-reviewed journals.

Trial registration number

NCT03449316; Pre-Results.

http://bit.ly/2Wqn3Xm

Multicomponent non-pharmacological intervention to prevent delirium for hospitalised people with advanced cancer: study protocol for a phase II cluster randomised controlled trial

Introduction

Delirium is a significant medical complication for hospitalised patients. Up to one-third of delirium episodes are preventable in older inpatients through non-pharmacological strategies that support essential human needs, such as physical and cognitive activity, sleep, hydration, vision and hearing. We hypothesised that a multicomponent intervention similarly may decrease delirium incidence, and/or its duration and severity, in inpatients with advanced cancer. Prior to a phase III trial, we aimed to determine if a multicomponent non-pharmacological delirium prevention intervention is feasible and acceptable for this specific inpatient group.

Methods and analysis

The study is a phase II cluster randomised wait-listed controlled trial involving inpatients with advanced cancer at four Australian palliative care inpatient units. Intervention sites will introduce delirium screening, diagnostic assessment and a multicomponent delirium prevention intervention with six domains of care: preserving natural sleep; maintaining optimal vision and hearing; optimising hydration; promoting communication, orientation and cognition; optimising mobility; and promoting family partnership. Interdisciplinary teams will tailor intervention delivery to each site and to patient need. Control sites will first introduce only delirium screening and diagnosis, later implementing the intervention, modified according to initial results. The primary outcome is adherence to the intervention during the first seven days of admission, measured for 40 consecutively admitted eligible patients. Secondary outcomes relate to fidelity and feasibility, acceptability and sustainability of the study intervention, processes and measures in this patient population, using quantitative and qualitative measures. Delirium incidence and severity will be measured to inform power calculations for a future phase III trial.

Ethics and dissemination

Ethical approval was obtained for all four sites. Trial results, qualitative substudy findings and implementation of the intervention will be submitted for publication in peer-reviewed journals, and reported at conferences, to study sites and key peak bodies.

Trial registration number

ACTRN12617001070325; Pre-results.

http://bit.ly/2RkEqVv

Role of intuitive knowledge in the diagnostic reasoning of hospital specialists: a focus group study

Background and objective

Intuition is an important part of human decision-making and can be explained by the dual-process theory where analytical and non-analytical reasoning processes continually interact. These processes can also be identified in physicians' diagnostic reasoning. The valuable role of intuition, including gut feelings, has been shown among general practitioners and nurses, but less is known about its role among hospital specialists. This study focused on the diagnostic reasoning of hospital specialists, how they value, experience and use intuition.

Design and participants

Twenty-eight hospital specialists in the Netherlands and Belgium participated in six focus groups. The discussions were recorded, transcribed verbatim and thematically coded. A circular and iterative analysis was applied until data saturation was achieved.

Results

Despite initial reservations regarding the term intuition, all participants agreed that intuition plays an important role in their diagnostic reasoning process. Many agreed that intuition could guide them, but were cautious not to be misguided. They were especially cautious since intuition does not have probative force, for example, in medicolegal situations. 'On-the-job experience' was regarded as a precondition to relying on intuition. Some participants viewed intuition as non-rational and invalid. All participants said that intuitive hunches must be followed by analytical reasoning. Cultural differences were not found. Both the doctor as a person and his/her specialty were seen as important determinants for using intuition.

Conclusions

Hospital specialists use intuitive elements in their diagnostic reasoning, in line with general human decision-making models. Nevertheless, they appear to disagree more on its role and value than previous research has shown among general practitioners. A better understanding of how to take advantage of intuition, while avoiding pitfalls, and how to develop 'skilled' intuition may improve the quality of hospital specialists' diagnostic reasoning.

http://bit.ly/2WqmLzK

Evaluation of influenza surveillance systems in sub-Saharan Africa: a systematic review protocol

Introduction

Influenza infrastructure systems are crucial for maintaining surveillance operations, and for mitigating and responding to the disease. The role of surveillance is to isolate and identify as rapidly as possible any new influenza strains and collate this information for the preparedness for, and response to, an impending influenza activity in humans. However, sources of surveillance information, particularly in Africa, are meagre. This systematic review will critically evaluate the existing influenza surveillance systems in sub-Saharan Africa.

Method and analysis

We will build multiple electronic database search strategies for use in PubMed, Scopus, African Journal Online, Web of Science and Google scholar to identify as many studies as possible. The medical subject heading and keywords will include a wide range of synonyms, both in index terms and free-text words. Database search will be followed by hand searching of reference lists of all relevant studies. We will include eligible full-text studies published from 2002 in order to coincide with the establishment of the integrated disease surveillance and response system in Africa by WHO. We will examine the influenza surveillance performance systems using the US Centers for Disease Control and Prevention guidelines on evaluating public health surveillance systems. Our outcome measures will include surveillance system attributes such as timeliness, sensitivity, specificity, acceptability, representativeness, simplicity and usefulness. We will conduct a narrative synthesis of all studies.

Ethics and dissemination

This study does not require ethics approval because it uses publicly available data. Our findings will be published in a peer review journal and disseminated to policy makers.

PROSPERO registration number

CRD42018103042.

http://bit.ly/2Rois4e

Comparative efficacy of interventions for reducing injection and sexual risk behaviours to prevent HIV in injection drug users: protocol for Bayesian network meta-analysis

Introduction

Drug users are more vulnerable to AIDS than the general population. While several interventions are effective for addressing HIV in injection drug users, no meta-analysis has yet been performed to compare interventions and determine the relative benefits of each. We intend to conduct a Bayesian network meta-analysis to compare all available interventions evaluated by a randomised controlled trial for reducing injection and risky sexual behaviours for the prevention of HIV in injection drug users.

Methods and analysis

Studies will be retrieved by searching the following databases: MEDLINE, Embase, PsycINFO and Cochrane Central Register of Controlled Trials. The search will be performed between May and July 2018 for the literature published between 1980 and May 2018. Two authors will extract data independently. Primary outcome measures will be injection risk behaviour and HIV risk behaviour. HIV seroconversion, confirmed using an antibody test, will be the secondary outcome. Bayesian network meta-analyses will be conducted using the Markov Chains Monte Carlo method. The Cochrane revised tool, Risk of Bias, will be used to assess the risk of bias. Grading of Recommendations Assessment, Development and Evaluation will be used to assess evidence quality.

Ethics and dissemination

The results of this study will be disseminated at professional conferences and via publications in peer-reviewed journals. This study will not include any confidential personal data or data on human trials; therefore, ethical approval is not required.

PROSPERO registration number

CRD42018086999.

http://bit.ly/2WqmH2Y

Hypersegmented airway neutrophils and its association with reduced lung function in adults with obstructive airway disease: an exploratory study

Objectives

The significance of neutrophilic inflammation in obstructive airway disease remains controversial. Recent studies have demonstrated presence of an active neutrophil population in systemic circulation, featuring hypersegmented morphology, with high oxidative burst and functional plasticity in inflammatory conditions. The aim of this study was to characterise neutrophil subsets in bronchial lavage (BL) of obstructive airway disease participants (asthma, chronic obstructive pulmonary disease (COPD) and bronchiectasis) and healthy controls on the basis of nuclear morphology and to assess the association between neutrophil subsets and the clinical parameters of the obstructive airway disease participants.

Design

A cross-sectional exploratory study.

Setting

John Hunter Hospital and Hunter Medical Research Institute, Australia.

Participants

Seventy-eight adults with obstructive airway disease comprised those with stable asthma (n=39), COPD (n=20) and bronchiectasis (n=19) and 20 healthy controls.

Materials and methods

Cytospins were prepared and neutrophil subsets were classified based on nuclear morphology into hypersegmented (>4 lobes), normal (2–4 lobes) and banded (1 lobe) neutrophils and enumerated.

Results

Neutrophils from each subset were identified in all participants. Numbers of hypersegmented neutrophils were elevated in participants with airway disease compared with healthy controls (p<0.001). Both the number and the proportion of hypersegmented neutrophils were highest in COPD participants (median (Q1–Q3) of 1073.6 (258.8–2742) x 10²/mL and 24.5 (14.0–46.5)%, respectively). An increased proportion of hypersegmented neutrophils in airway disease participants was significantly associated with lower forced expiratory volume in 1 s/forced vital capacity per cent (Spearman's r=–0.322, p=0.004).

Conclusion

Neutrophil heterogeneity is common in BL and is associated with more severe airflow obstruction in adults with airway disease. Further work is required to elucidate the functional consequences of hypersegmented neutrophils in the pathogenesis of disease.

http://bit.ly/2Rk7Lzy

Cohort profile: the Swedish Prescribed Drugs and Health Cohort (SPREDH)

Purpose

The Swedish Prescribed Drugs and Health Cohort (SPREDH) is a Swedish population-based cohort based on data from four nationwide health data registers, created with the aim of investigating how the use of selected medications influences cancer risk and other outcomes.

Participants

The cohort includes 8 421 115 users of selected common medications who have been followed-up for a total of 82 281 720 person-years from 1 July 2005 to 31 December 2015.

Finding to date

The data in SPREDH were prospectively collected from the following national health data registers in Sweden: Prescribed Drug Register, Patient Register, Cancer Register and Causes of Death Register. Data on basic patient characteristics, use of the selected common medications, healthcare utilisation, diagnoses (including detailed information on cancers), and dates and causes of death are available for all cohort participants. The cohort currently includes 801 766 incident cancer cases.

Future plans

The data in SPREDH can be used for various types of epidemiological research, particularly for examining how the use of the selected medications influences disease risk and other outcomes. We are initially planning cohort studies and nested case-control studies on selected medications in relation to the risk and prognosis of oesophageal and gastric cancers.

http://bit.ly/2WqmUTO

Understanding care when cure is not likely for young adults who face cancer: a realist analysis of data from patients, families and healthcare professionals

Objectives

To understand the experiences of young adults with cancer for whom cure is not likely, in particular what may be specific for people aged 16–40 years and how this might affect care.

Design

We used data from multiple sources (semi-structured interviews with people with cancer, nominated family members and healthcare professionals, and workshops) informed by a preliminary programme theory: realist analysis of data within these themes enabled revision of our theory. A realist logic of analysis explored contexts and mechanisms affecting outcomes of care.

Setting

Three cancer centres and associated palliative care services across England.

Participants

We aimed for a purposive sample of 45 people with cancer from two groups: those aged 16–24 years for whom there may be specialist cancer centres and those 16–40 years cared for through general adult services; each could nominate for interview one family member and one healthcare professional. We interviewed three people aged 16–24 years and 30 people 25–40 years diagnosed with cancer (carcinomas; blood cancers; sarcoma; central nervous system tumours) with a clinician-estimated prognosis of <12 months along with nominated family carers and healthcare professionals. 19 bereaved family members and 47 healthcare professionals participated in workshops.

Results

Data were available from 69 interviews (33 people with cancer, 14 family carers, 22 healthcare professionals) and six workshops. Qualitative analysis revealed seven key themes: loss of control; maintenance of normal life; continuity of care; support for professionals; support for families; importance of language chosen by professionals; and financial concerns.

Conclusions

Current care towards end of life for young adults with cancer and their families does not meet needs and expectations. We identified challenges specific to those aged 16–40 years. The burden that care delivery imposes on healthcare professionals must be recognised. These findings can inform recommendations for measures to be incorporated into services.

http://bit.ly/2RpuzxI

Is microfinance associated with changes in womens well-being and childrens nutrition? A systematic review and meta-analysis

Background

Microfinance is the provision of savings and small loans services, with no physical collateral. Most recipients are disadvantaged women. The social and health impacts of microfinance have not been comprehensively evaluated.

Objective

To explore the impact of microfinance on contraceptive use, female empowerment and children's nutrition in South Asia, Sub-Saharan Africa and Latin America and the Caribbean.

Design

We conducted a systematic search of published and grey literature (1990–2018), with no language restrictions. We conducted meta-analysis, where possible, to calculate pooled ORs. Where studies could not be combined, we described these qualitatively.

Data sources

EMBASE, MEDLINE, LILACS, CENTRAL and ECONLIT were searched (1990–June 2018).

Eligibility criteria

We included controlled trials, observational studies and panel data analyses investigating microfinance involving women and children.

Data extraction and synthesis

Two independent reviewers extracted data and assessed risk of bias. The methodological quality of included studies was assessed using the Cochrane risk-of-bias tool for controlled trials and quasi-experimental studies and a modified Newcastle Ottawa Scale for cross-sectional surveys and analyses of panel data. Meta-analyses were conducted using STATA V.15 (StataCorp).

Results

We included 27 studies. Microfinance was associated with a 64% increase in the number of women using contraceptives (OR 1.64, 95% CI 1.45 to 1.86). We found mixed results for the association between microfinance and intimate partner violence. Some positive changes were noted in female empowerment. Improvements in children's nutrition were noted in three studies.

Conclusion

Microfinance has the potential to generate changes in contraceptive use, female empowerment and children's nutrition. It was not possible to compare microfinance models due to the small numbers of studies. More rigorous evidence is needed to evaluate the association between microfinance and social and health outcomes.

PROSPERO registration number

CRD42015026018.

http://bit.ly/2WrmFI7

Native American patients perception and attitude about kidney transplant: a qualitative assessment of patients presenting for kidney transplant evaluation

Objective

Native Americans suffer from lower rates of kidney transplantation compared with whites. Our goal was to elicit patients' perceptions of and attitudes about kidney transplant and the impact of financial burden and cultural taboos.

Design

This is an exploratory qualitative interview study of 12 Native American patients recruited after completion of the kidney transplant evaluation.

Setting

Semistructured interviews were conducted. Interviews were coded using inductive methods, followed by interpretive coding by the investigators.

Results

Thematic analysis revealed the following themes: (1) experience with kidney transplant education by the healthcare team; (2) cultural beliefs regarding kidney transplant; (3) personal motivation and attitude towards kidney transplant; (4) financial burden of kidney transplant and post-transplant care and (5) attitude about living donation.

Most participants were educated about transplant as a treatment option after dialysis initiation. All patients in this study recognised that some taboos exist about the process of organ procurement and transplantation; however, the traditional views did not negatively impact their decision to pursue kidney transplant evaluation. Patients shared the common theme of preferring an organ from a living rather than a deceased person; however, the majority did not have a living donor and preferred not to receive an organ from a family member. Most patients did not perceive transplant-related cost as negatively impacting their attitude about receiving a transplant even for patients with below poverty level income.

Conclusions

Native American patients presenting for kidney transplant were less likely to be educated about transplant before dialysis initiation; did not perceive financial burden and cultural beliefs were not discussed as obstacles to transplant. While a living donor was the preferred option, enthusiasm for living donation from family members was limited.

http://bit.ly/2RmuQSj

Impact of educational attainment on the association between social class at birth and multimorbidity in middle age in the Aberdeen Children of the 1950s cohort study

Objective

Multimorbidity (the coexistence of two or more health conditions) is increasingly prevalent. No long-term cohort study has examined the impact of contemporaneously measured birth social class along with educational attainment on adult self-reported multimorbidity. We investigated the impact of educational attainment on the relationship between social class at birth and adult self-reported multimorbidity in the Aberdeen Children of the 1950s (ACONF) cohort.

Methods

A prospective cohort study using the ACONF cohort. ACONF included 12 150 individuals born in Aberdeen, Scotland 1950–1956. In 2001, 7184 (64%) responded to a questionnaire providing information including self-reported morbidity and educational attainment. The exposure was father's social class at birth from birth records and the outcome was self-reported multimorbidity.

Logistic regression assessed the association between social class and multimorbidity with adjustment for gender, then by educational attainment and finally by childhood cognition and secondary school type. ORs and 95% CIs were presented.

Results

Of 7184 individuals (mean age 48, 52% female), 5.4% reported multimorbidity. Birth social class was associated with adult multimorbidity. For example, the OR of multimorbidity adjusted by gender was 0.62 (95% CI 0.39 to 1.00) in the highest social class group (I/II) in relation to the reference group (III (manual)) and was 1.85 (95% CI 1.19 to 2.88) in the lowest social class group. This was partially attenuated in all social class categories by educational attainment, for example, the OR was 0.74 (95% CI 0.45 to 1.21) in group I/II following adjustment.

Conclusion

Lower social class at birth was associated with developing multimorbidity in middle age. This was partially mediated by educational attainment and future research should consider identifying the other explanatory variables. The results are relevant to researchers and to those aiming to reduce the impact of multimorbidity.

http://bit.ly/2Wqmxso

Are there gender differences in acute management and secondary prevention of acute coronary syndromes in Barbados? A cohort study

Objectives

In Barbados, high case fatality rates have been reported after myocardial infarction (MI) with higher rates in women than men. To explore this inequality, we examined documented pharmacological interventions for ST-segment elevated myocardial infarction (STEMI), non-STEMI (NSTEMI) and unstable and chronic angina in women and men.

Design

Prospective cohort registry data for STEMI and NSTEMI and retrospective chart review for unstable and chronic angina.

Setting

Tertiary care (acute coronary syndromes) and primary care (chronic angina) centres in Barbados.

Participants

For the years 2009–2016, a total of 1018 patients with STEMI or NSTEMI were identified via the prospective study. For unstable and chronic angina, 136 and 272 notes were reviewed respectively for the years 2010–2014.

Outcome measures

The proportions of patients prescribed recommended medication during the first 24 hours after an acute event, at discharge and for chronic care were calculated. Prescribed proportions were analysed by gender after adjustment for age.

Results

Between 2009 and 2016, for the acute management of patients with NSTEMI and STEMI, only two (aspirin and clopidogrel) of six drugs had documented prescription rates of 80% or more. Patients with STEMI (n=552) had higher prescription rates than NSTEMI (n=466), with gender differences being more pronounced in the former. Among patients with STEMI, after adjustment for age, diabetes, hypertension and smoking, men were more likely to receive fibrinolytics acutely, OR 2.28 (95% CI 1.24 to 4.21). Compared with men, a higher proportion of women were discharged on all recommended treatments; this was only statistically significant for beta-blockers: age-adjusted OR 1.87 (95% CI 1.16 to 3.00). There were no statistically significant differences in documented prescription of drugs for chronic angina.

Conclusion

Following acute MI in Barbados, the proportion of patients with documented recommended treatment is relatively low. Although women were less likely to receive appropriate acute care than men, by discharge gender differences were reversed.

http://bit.ly/2RnLBwe

Lenvatinib plus everolimus or pembrolizumab versus sunitinib in advanced renal cell carcinoma: study design and rationale

Future Oncology, Ahead of Print.


http://bit.ly/2WqhCYa

Very rare case of synchronous volvulus of the sigmoid colon and caecum causing large-bowel obstruction

Large-bowel obstruction caused by volvulus is potentially life threatening if not managed promptly. Sigmoid colon is the most common site of volvulus followed by caecum. Synchronous double colonic volvulus is an exceedingly rare entity, with only five cases published previously. We present the case of a 77-year-old man with a synchronous sigmoid and caecal volvulus. He underwent total colectomy with ileostomy formation with a view to reverse the ileostomy at a later date.

http://bit.ly/2CQrzFt

Rectal bleeding caused by a syphilitic inflammatory mass

A 47-year-old man presented with fatigue, decrease appetite, abdominal pain and rectal bleeding. His colonoscopy revealed a single, firm, raised, centrally ulcerated mass at the anorectal junction. During this same admission, he was diagnosed with HIV and syphilis, found to have multiple hepatic lesions and positive cerebrospinal fluidvenereal disease research laboratory test (VDRL). Biopsies from both the hepatic lesions and rectal ulcer showed spirochaetes by immunostaining. The initial presentation was felt to be secondary to a rectal inflammatory mass caused by syphilis.

http://bit.ly/2CP5qHJ

Acute blue finger syndrome: a rare benign cause of acute digit discolouration

Acute blue finger syndrome is a rare benign condition that mimics digital ischaemia. We discuss the case of a 32-year-old woman who presented with a 6hour history of blue discolouration of the middle finger of the right hand, associated with pain and swelling. There was no history of trauma and this was the first time that the patient had experienced these symptoms. Examination found blue discolouration of the digit primarily on the volar aspect with associated swelling. All investigations, including blood tests, X-rays and Doppler scanning, were normal. The symptoms resolved spontaneously within 48 hours. There were no recurrent episodes or long-term sequelae. Patients presenting with an acutely blue finger need rapid assessment to exclude digit ischaemia. Knowledge of this rare benign condition may prevent unnecessary distress, invasive investigations and potentially harmful treatment of a healthy patient.

http://bit.ly/2CS80N6

Examination under anaesthesia of the rectum for removal of gallstones

http://bit.ly/2RXWGcH

Rare case with plethora of upper urinary tract anomalies associated with pelviureteric junction obstruction: a surgical challenge managed with robot assistance

The genitourinary system for reasons unknown is more likely to have birth defects than any other system. The anomaly of collecting system draining the kidney represent mystifying subset of congenital anomalies. Pelviureteric junction obstruction (PUJO) is most common. Chronic obstruction can lead to stasis, urinary infection and stone formation in PUJO. Extrarenal calyces, which is characterised by presence of calyces and renal pelvis outside the renal parenchyma is one of the rare anomalies seen among the collecting system right gonadal vein drains into inferior vena cava. Its altered drainage into right renal vein is rarely seen and reported. Glut of these multiple anomalies in a single case is an extremely rare event. We hereby discuss a case of 40-year-old male patient with combination of all these anomalies and discuss the embryology, presentation and management.

http://bit.ly/2CTrJMt

Primary Ewing sarcoma of the kidney

Primary Ewing sarcoma (ES) or primitive neuroectodermal tumour (PNET) is a rare tumour in adults and primary renal involvement is extremely rare. Patients with renal ES or PNET respond to and would benefit from conventional ES treatment according to ES study protocols. Here, we report a case of a young woman, presenting with right flank pain and haematuria. After ultrasound and CT evaluation, a right middle pole renal mass was detected. The patient underwent radical right nephrectomy, and a grade 4 ES with peritoneal involvement was documented. Subsequently, the patient underwent adjuvant chemotherapy for 5 months. Follow-up 18F-fluorodeoxyglucose (FDG) positron emission tomography (PET)/CT scan demonstrated bilateral cervical, hilar, mediastinal and retroperitoneal FDG-avid adenopathies associated with mild right-sided pleural effusion with no metabolic activity, signifying the role of PET/CT scan in tumour restaging.

http://bit.ly/2RU0Lyh

Ileal conduit volvulus: rare complication of urinary diversion

Ileal conduit volvulus is a rare complication of urinary diversion. It has been suggested that various factors including prolonged length of the ileal segment, lack of fixation of the conduit to the peritoneum and failure to close the incised mesentery predispose patients to this complication. We present the case of a 76-year-old man who presented to hospital with severe abdominal pain and oliguria secondary to a volvulus of his ileal conduit. Investigations revealed early acute kidney injury as a result of urinary obstruction which was evident on abdominal CT. The patient subsequently underwent operative repair of the volvulus. Symptoms resolved following the procedure, kidney function improved and the patient was discharged without complication.

http://bit.ly/2CRvLVj

Peroneal artery entrapment syndrome (PRAES): a rare cause of ischaemic toes

A 75-year-old man presenting with intermittent discolouration of his left toes was referred to vascular surgery with suspicion of embolic vascular disease. A contrast-enhanced MR angiogram was performed which revealed bilateral dominant peroneal arteries (PRAs). There was evidence of short atherosclerotic stenosis directly at the point where the left PRA passes through the tibiofibular interosseous membrane which we postulate to be the source of the emboli. We present what is believed to be the first reported case of PRA entrapment complicated by distal toe emboli.

http://bit.ly/2CQlMQc

Behavioural changes as the first manifestation of a silent frontal lobe stroke

A 67-year-old man was admitted to our hospital after his relatives found him to have severe personality and behavioural changes. His behaviour was inappropriate and uninhibited. The patient reported no symptoms and he showed poor insight into his own behaviour. Neuroimaging showed an orbitofrontal lesion, due to an infarction of the anterior cerebral artery. The patient was diagnosed with frontal lobe syndrome.

http://bit.ly/2RXWvy3

Pseudomonas meningoencephalitis masquerading as a stroke in a patient on tocilizumab

A previously high-functioning woman presents with clinical and CT features of a subacute ischaemic stroke. Her medical history is relevant for refractory giant cell arteritis on long-term high-dose prednisolone and recent commencement of tocilizumab (interleukin-6 monoclonal antibody). The potential for stroke mimic is considered and a magnetic resonance brain scan is requested. She rapidly deteriorates within 24 hours of admission and unexpectantly dies. An autopsy reveals that she has bilateral pulmonary emboli with lower limb deep vein thrombosis and Pseudomonas meningoencephalitis with frank pus on the brain. We discuss the potential risks of immunosuppression and the role of imaging in the diagnosis of stroke.

http://bit.ly/2RRIeCZ

Intestinal obstruction caused by small bowel adenocarcinoma misdiagnosed as psychogenic disorder

We describe a case of intestinal obstruction caused by a small bowel adenocarcinoma misdiagnosed as psychogenic disorder. A woman in her 40s was admitted to Nagoya City University Hospital with fatigue, anorexia, nausea and vomiting. CT, oesophagogastroduodenoscopy and colonoscopy revealed no signs of organic abnormality in her gastrointestinal tract. As the patient had previously been diagnosed with and treated for depression, her symptoms were suspected to be due to psychogenic disorder. Therefore, she was diagnosed with severe depression and was administered antidepressant agents. Despite intense psychiatric treatment, her symptoms worsened and she was later diagnosed with ileus due to adenocarcinoma in the jejunum. After drainage by insertion of a transnasal decompression tube, a partial jejunum resection was performed. After the resection, the patient's symptoms including fatigue and depression resolved without the use of antidepressant agents.

http://bit.ly/2CPLoNi

Simultaneous presentation of thyroid storm and diabetic ketoacidosis in a previously healthy 21-year-old man

A 21-year-old young man with no history of diabetes or thyroid disease presented to the emergency department with simultaneous thyroid storm and diabetic ketoacidosis. Notable findings on admission were a ventricular rate of 235 beats/min, tachypnoea, tremors, polydipsia and a lack of fever. Due to the unusual constellation of symptoms, diagnosis was only possible after initial laboratory results came back. While the lack of fever is unusual in thyroid storm, diabetic ketoacidosis has previously been reported to suppress fever, and this case supports the occurrence of this phenomenon. This case was highly unusual because the patient had not previously been diagnosed with either type 1 diabetes or Graves' disease.

http://bit.ly/2RRMm5M

Hypocalcaemia and hyponatraemia masquerading the diagnosis of Gitelman syndrome

Gitelman syndrome is the most common renal tubulopathy, recently exhibiting a dramatic rise of incidence in Asia.

A 50-year-old woman presented with vomiting, fatigue and quadriparesis. Physical examination revealed a positive Trousseau sign , hypotonia and areflexia.

Suspecting hypocalcaemia, she was given intravenous 10% calcium gluconate (10 mL administered slowly over 10 min) but her manifestations persisted. An exhaustive laboratory work up revealed the diagnosis of Gitelman syndrome.

The peculiarity of this case however, is entailed in its coexistence with hypocalcaemia and hyponatraemia. In addition, the age of primary presentation being 50 years further culminates its atypicality.

Multiple electrolyte imbalances were corrected by oral and intravenous supplementation and a high sodium-potassium diet was advocated. Administration of spironolactone imposed a pitfall in the management of our patient due to exacerbation of pre-existing hyponatraemia.

On follow-up, her electrolyte profile was stable and corresponding symptoms were alleviated.

http://bit.ly/2RSmzdG

Aortitis and pachymeningitis: an unusual combination in granulomatosis with polyangiitis (myeloperoxidase-associated vasculitis)

Aortitis and pachymeningitis are uncommon manifestations of the antineutrophil cytoplasmic antibody-associated vasculitides, a group of systemic autoimmune diseases mainly affecting small vessels. We present a case of a 71-year-old woman with a remote history of idiopathic chronic granulomatous pachymeningitis complicated with aortic thickening due to autoimmune aortitis.

http://bit.ly/2CTQR5u

Hepatitis in patients with syphilis: an overlooked association

We present the case of a patient who sought treatment for fever and a maculopapular rash involving the trunk, limbs, palms and soles. The patient also presented with hepatomegaly and elevated levels of liver enzymes (with a higher increase of alkaline phosphatase). With the proposal of early syphilitic hepatitis, during the stage of secondary syphilis, a venereal disease research laboratory and Treponema pallidum haemagglutination tests were requested, which confirmed the diagnosis. All altered parameters improved with antibiotic treatment for secondary syphilis. Syphilitic hepatitis is an often overlooked presentation of syphilis and should be considered as a differential diagnosis in patients with elevated levels of liver enzymes and risk factors for syphilis.

http://bit.ly/2RXztXW

Actinomycosis of the omentum with invasion of the abdominal wall, small bowel and transverse colon mimicking malignancy

We report the case of a 59-year-old Russian man who presented with a painless, slow-growing, epigastric mass. CT revealed a large heterogeneous mass within the omentum infiltrating into adjacent tissues. During diagnostic laparoscopy, the omental mass was noted to be firm, raising the suspicion of malignancy. Surgical en-bloc resection of the mass, including the posterior rectus sheath, transverse colon and small bowel, was performed with primary anastomoses at laparotomy. Histological examination was inconsistent with malignancy and revealed the mass to be actinomycosis, confirmed by microscopy and gram staining. Surgical resection was followed by an 8-week course of penicillin and doxycycline antibiotic therapy. This treatment resulted in full clinical and radiological recovery with no complications. Although the clinical and radiological findings, in this case, were highly suspicious of malignancy, abdominal actinomycosis should be considered a differential diagnosis in patients with infiltrative abdominal masses and mild constitutional symptoms.

http://bit.ly/2CM1jfe

Largest giant juvenile fibroadenoma of the breast

Juvenile giant fibroadenoma is a rare benign tumour of the breast accounting for 0.5% of all fibroadenomas. The presentation can be very dramatic and may result in breast deformity and may mimic a rare malignant tumour. It is indeed a great challenge to provide the best treatment for these patients in terms of clinical and psychological care. Meticulous surgical planning is required to ensure a fine balance between adequate resection and the best cosmetic outcome for a developing breast. Every effort should be made to preserve the developing breast irrespective of the size of the tumour as it is in this case. We report the world's largest juvenile fibroadenoma of the breast in a 16-year-old girl who presented to our hospital with a 28x25 cm mass on her left breast in which breast conservation was done. A detailed literature search and management of these lesions are discussed.

http://bit.ly/2RXW86D

Nodular scleritis with strongly positive serum rheumatoid factor: forme fruste rheumatoid arthritis sans arthritis

http://bit.ly/2RTSRoM

Unmet Clinical Need in the Management of Locally Advanced Unresectable Lung Cancer: Treatment Strategies to Improve Patient Outcomes

Abstract

Stage III locally advanced non-small cell lung cancer (LA NSCLC) comprises the most heterogeneous group of patients, accounts for one-third of patients with lung cancer, and is unresectable at presentation. Multiple treatment approaches have evolved over the past few decades focusing on timing of chemoradiation (concurrent vs. sequential) and sequencing of therapy (induction vs. consolidation). Concurrent chemoradiation (CCRT) emerged as the standard of care for the majority of the patients worldwide. Despite improvements in median and overall survival (OS) using the concurrent approach, the rate of distant failure remains high. Consolidation with chemotherapy or targeted agents, adding more radiation dose, or induction chemotherapy did not improve OS. With continued research on defining optimal radiation doses and schedules and integrating novel systemic agents, immunotherapy consolidation has renewed optimism. Synergistic use of radiation and immunotherapy can prevent micrometastatic disease and reduce local failure and may have an abscopal effect in addition to survival benefits. The PACIFIC study reported an absolute progression-free survival benefit of 11.2 months with durvalumab consolidation after standard CCRT compared with placebo. The OS data with durvalumab consolidation are encouraging. Durvalumab is the only approved immunotherapy for unresectable stage III LA NSCLC. Improved survival confirms the definitive role of durvalumab as an effective adjuvant therapy after CCRT with no new safety signals. However, the potential mechanisms driving interaction between immunotherapy and chemoradiotherapy require definitive investigation. These mechanisms may help define the timing of immunotherapy initiation as neoadjuvant, adjuvant, or consolidation and maintenance therapy after progression.

Funding

AstraZeneca Pharma India Limited.

http://bit.ly/2RUf8mh

Sex-Specific Co-expression Networks and Sex-Biased Gene Expression in the Salmonid Brook Charr Salvelinus fontinalis

Networks of co-expressed genes produce complex phenotypes associated with functional novelty. Sex differences in gene expression levels or in the structure of gene co-expression networks can cause sexual dimorphism and may resolve sexually antagonistic selection. Here we used RNA-sequencing in the salmonid Brook Charr Salvelinus fontinalis to characterize sex-specific co-expression networks in the liver of 47 female and 53 male offspring. In both networks, modules were characterized for functional enrichment, hub gene identification, and associations with 15 growth, reproduction, and stress-related phenotypes. Modules were then evaluated for preservation in the opposite sex, and in the congener Arctic Charr Salvelinus alpinus. Overall, more transcripts were assigned to a module in the female network than in the male network, which coincided with higher inter-individual gene expression and phenotype variation in the females. Most modules were preserved between sexes and species, including those involved in conserved cellular processes (e.g. translation, immune pathways). However, two sex-specific male modules were identified, and these may contribute to sexual dimorphism. To compare with the network analysis, differentially expressed transcripts were identified between the sexes, revealing a total of 16% of expressed transcripts as sex-biased. For both sexes, there was no overrepresentation of sex-biased genes or sex-specific modules on the putative sex chromosome. Sex-biased transcripts were also not overrepresented in sex-specific modules, and in fact highly male-biased transcripts were enriched in preserved modules. Comparative network analysis and differential expression analyses identified different aspects of sex differences in gene expression, and both provided new insights on the genes underlying sexual dimorphism in the salmonid Brook Charr.

http://bit.ly/2FUqqR4

Exenatide Delays Gastric Emptying in Patients with Type 2 Diabetes Mellitus but not in Those with Gastroparetic Conditions

Horm Metab Res
DOI: 10.1055/a-0818-6374

The effect of the treatment with glucagon-like peptide (GLP)-1 receptor agonists on gastric emptying in patients with diabetes with and without gastroparesis is analysed. Patients with type 2 diabetes mellitus subjected to GLP-1 receptor agonist therapy with exenatide were examined before and shortly after initiation of treatment. Gastric half-emptying time was determined by 13C-octanoic breath test; routine laboratory parameter as well as active GLP-1, ghrelin, leptin, insulin, proinsulin and C-peptide levels were determined in fasting state as well as postprandial secretion within 1 h after a standardised meal. Thirty patients' data sets were available for evaluation, of those 20 patients had no gastroparesis and 10 patients showed pathological results following the breath test. Gastric half-emptying time was prolonged in nearly all patients who presented without gastroparesis at initiation of treatment with GLP-1 receptor agonists, only 2 patients with pre-existing mild gastroparesis had worsening of gastric emptying. No effect was detected on leptin and ghrelin levels. Postprandial GLP-1 concentrations measured as AUC after meal decreased significantly. Fasting insulin and C-peptide levels increased significantly without effect on postprandial levels. Proinsulin levels – fasting as well as AUC – decreased non-significantly. Patients reported comparable perception of therapeutic effects. Treatment with GLP-1 receptor agonists may be applied in patients with pre-existing gastroparesis; no effect in terms of worsening of symptoms compared to those without gastroparesis was detected. Patients reported outcome was independent from underlying gastroparesis. Negative effects on gastric emptying were only detected in patients without or with mild gastroparesis.
[...]

© Georg Thieme Verlag KG Stuttgart · New York

Article in Thieme eJournals:
Table of contents  |  Abstract  |  Full text

http://bit.ly/2G7twR1

Spraying l‐menthol enhances gastric intestinal metaplasia in linked color imaging

Abstract

Recently, there have been some reports that image‐enhanced endoscopy (IEE) may be useful for detection of gastric intestinal metaplasia (GIM) (1, 2). Linked color imaging (LCI) enables noninvasive detection of GIM as a lavender color, which is called lavender color sign (LCS) (3). Spraying l‐menthol directly onto the gastric antral mucosa is useful for anti‐peristalsis. As a secondary effect of spraying l‐menthol, Mori et al. reported annular‐reticular‐like mucosal changes that were mucosal morphologic changes.

This article is protected by copyright. All rights reserved.

http://bit.ly/2RVrFGf

A case of non‐ampullary duodenal adenoma showing whitish color changes during potassium‐competitive acid blocker treatment

Abstract

A 71‐year‐old male presented with suspected gastric cancer during screening. Esophagogastroduodenoscopy (EGD) revealed a slightly decolored flat lesion (diameter: 5 mm) on the duodenal bulb (Fig. 1a). On magnifying endoscopy with narrow‐band imaging (M‐NBI), meandering microvessels were visualized (Fig. 1b).

This article is protected by copyright. All rights reserved.

http://bit.ly/2UsbWvd

Biliary interventions using Single operator cholangioscopy

Abstract

Cholangioscopy provides an opportunity to directly visualize the bile duct for diagnosing biliary lesions and for therapeutic interventions. Although there are different cholangioscopy techniques available, single‐operator cholangiosopy has gained widespread acceptance as the standard technique for interventions in the biliary system because of its ease of use and widespread availability. Single‐operator cholangioscopy can be used for both diagnostic and therapeutic indications in the biliary tract. Diagnostic cholangioscopy is used for direct evaluation of indeterminate bile duct strictures with biopsies, diagnosing filling defects in the bile ducts observed during endoscopic retrograde cholangiography (ERC) imaging, preoperative mapping of the precise location and extension of tumors of the biliary tract and diagnosis of intraductal neoplasms. Therapeutic cholangioscopy is used for visually guided treatment of biliary stones that have failed extraction with conventional ERC techniques, residual or impacted stones by using intraductal lithotripsy, ablation of biliary tumors and for facilitation of guidewire advancement into selective intrahepatic ducts for adequate biliary drainage. In this review, we will focus on advances in the single‐operator cholangioscopy techniques in the diagnosis and management of biliary disorders.

This article is protected by copyright. All rights reserved.

http://bit.ly/2CSwp4S

Meta‐analysis of clinical outcome after treatment for achalasia based on manometric subtypes

Background

The introduction of high‐resolution manometry and the Chicago classification has made it possible to diagnose achalasia and predict treatment response accurately. The aim of this study was to compare the effect of the different treatments available on symptomatic outcomes across all achalasia subtypes.

Methods

The study was conducted according to PRISMA and MOOSE guidelines. A literature search of PubMed and MEDLINE databases was undertaken to identify all relevant articles reporting clinical outcomes of patients with achalasia after botulinum toxin injection, pneumatic dilatation, laparoscopic Heller myotomy (LHM) and peroral endoscopic myotomy (POEM) based on manometric subtypes. Patients were grouped according to the Chicago classification and the success rate in treating symptoms was measured as the primary endpoint.

Results

Twenty studies (1575 patients) were selected, and data on botulinum toxin, pneumatic dilatation, LHM and POEM were extracted. Success rates for LHM in type I, II and III achalasia were 81, 92 and 71 per cent respectively. Those for POEM were 95, 97 and 93 per cent respectively. POEM was more likely to be successful than LHM for both type I (odds ratio (OR) 2·97, 95 per cent c.i. 1·09 to 8·03; P = 0·032) and type III (OR 3·50, 1·39 to 8·77; P = 0·007) achalasia. The likelihood of success of POEM and LHM for type II achalasia was similar.

Conclusion

Pneumatic dilatation had a lower but still acceptable success rate compared with POEM or LHM in patients with type II achalasia. POEM is an excellent treatment modality for type I and type III achalasia, although it did not show any superiority over LHM for type II achalasia.

http://bit.ly/2FV06qg

The transcriptional regulator Sin3A contributes to the oncogenic potential of STAT3

Epigenetic silencing of promoter and enhancer regions is a common phenomenon in malignant cells. The transcription factor Signal transducer and activator of transcription (STAT) 3 is aberrantly activated in several tumors, where its constitutive acetylation accounts for the transcriptional repression of a number of tumor suppressor genes (TSG) via molecular mechanisms that remain to be understood. Using NPM-ALK+ ALCL as model system, we found in cells and patient-derived tumor xenografts that STAT3 is constitutively acetylated as a result of ALK activity. STAT3 acetylation relied on intact ALK-induced PI3K- and mTORC1-dependent signaling and was sensitive to resveratrol. Resveratrol lowered STAT3 acetylation, rescued TSG expression, and induced ALCL apoptotic cell death. STAT3 constitutively bound the Sin3A transcriptional repressor complex, and both STAT3 and Sin3A bound the promoter region of silenced TSG via a resveratrol-sensitive mechanism. Silencing SIN3A caused re-expression of TSG, induced ALCL apoptotic cell death in vitro, and hindered ALCL tumorigenic potential in vivo. A constitutive STAT3-Sin3A interaction was also found in breast adenocarcinoma cells and proved critical for TSG silencing and cell survival. Collectively, these results suggest that oncogene-driven STAT3 acetylation and its constitutive association with Sin3A represent novel and concomitant events contributing to STAT3 oncogenic potential.

http://bit.ly/2FVF4rv

Cognate Non-Lytic Interactions between CD8+ T cells and Breast Cancer Cells Induce Cancer Stem Cell-like Properties

Targeting of tumor immune escape mechanisms holds enormous therapeutic potential. Still, most patients progress under immune checkpoint blockade and some even become hyper-progressors. To investigate how cancer cells respond to activated but ineffective T cells, we challenged peptide-loaded MCF-7 breast cancer cells with antigen-specific CD8+ T cells in which lytic granules had been destroyed by pre-treatment with Concanamycin A. Gene expression analysis after coculture revealed simultaneous induction of PD-L1, IDO1, CEACAM1, and further immunoregulatory checkpoints in breast cancer cells. Strikingly, we further observed gene signatures characteristic for dedifferentiation and acquisition of pluripotency markers including Yamanaka factors. Cognate interaction with non-lytic CD8+ T cells also increased the proportion of stem cell-like cancer cells in a cell-cell-contact- or (at least) proximity-dependent manner in various cell lines and in primary breast cancer cell cultures; this induction of stem cell-like properties was confirmed by enhanced tumor formation capacity in immunodeficient mice. Resulting tumors were characterized by enhanced cell density, higher proliferation rates, and increased propensity for lymphoid metastasis. These findings describe a widely underappreciated pathway for immune escape, namely immune-mediated dedifferentiation of breast cancer cells, which is associated with profound changes in gene expression and cellular behavior. As the enhanced malignant potential of cancer cells after non-lytic cognate interactions with CD8+ T cells enables increased tumor growth and metastasis in BALB/cnu/nu mice, the described mechanism may provide a possible explanation for the clinical phenomenon of hyperprogression in response to unsuccessful immunotherapy.

http://bit.ly/2G8ABB8

Local delivery of OX40L, CD80, and CD86 mRNA kindles global anti-cancer immunity.

Localized expression of effector molecules can initiate anti-tumor responses through engagement of specific receptors on target cells in the tumor microenvironment. These locally induced responses may also have a systemic effect, clearing additional tumors throughout the body. In this study, to evoke systemic anti-tumor responses, we utilized charge-altering releasable transporters (CART) for local intratumoral delivery of mRNA coding for co-stimulatory and immune-modulating factors. Intratumoral injection of the CART-mRNA complexes resulted in mRNA expression at the site of administration, transfecting a substantial proportion of tumor-infiltrating dendritic cells, macrophages, and T cells in addition to the tumor cells, resulting in a local anti-tumor effect. Using a two-tumor model, we further show that mRNA therapy locally administered to one tumor stimulated a systemic anti-tumor response, curing both tumors. The combination of OX40L-, CD80-, and CD86-encoding mRNA resulted in the local upregulation of pro-inflammatory cytokines, robust local T cell activation, and migration of immune cells to local draining lymph node or to an anatomically distant tumor. This approach delayed tumor growth, facilitated tumor regression, and cured tumors in both A20 and CT26 tumor models. These results highlight mRNA-CART therapy as a viable approach to induce systemic anti-tumor immunity from a single localized injection.

http://bit.ly/2FTHrLm

Susceptibility of mecillinam in Enterobacterales - results from a prospective in vitro study [Susceptibility]

The activity of mecillinam was assessed in Enterobacterales (n=420) isolated from urines in 2016/2017. Mecillinam susceptibility was 97.4% in E. coli (294/302), 89.7% in Klebsiella spp. (52/58) and 93.3 % in Proteus mirabilis (28/30). Among ESBL producers 95.2% (99/104) were mecillinam susceptible, including two OXA-48-producing K. pneumoniae. In Enterobacter spp. and Citrobacter spp., minimal inhibitory concentration were low (MIC₅₀=0.5 mg/L). In conclusion, the activity of mecillinam was high in Enterobacterales, even among multidrug-resistant isolates.

http://bit.ly/2B4jGfl

In vitro activity of a novel antifungal compound, MYC-053, against clinically significant antifungal-resistant strains of Candida glabrata, Candida auris, Cryptococcus neoformans, and Pneumocystis spp. [Experimental Therapeutics]

An urgent need exists for new antifungal compounds to treat fungal infections in immunocompromised patients. The aim of the current study was to investigate the potency of a novel antifungal compound, MYC-053, against the emerging yeast and yeast-like pathogens Candida glabrata, Candida auris, Cryptococcus neoformans, and Pneumocystis spp. MYC-053 was equally effective against the susceptible control strains, clinical isolates, and resistant strains, with the minimum inhibitory concentrations (MIC) of 0.125–4.0 μg/mL. Notably, unlike other antifungals such as azoles, polyenes and echinocandins, MYC-053 was effective against Pneumocystis isolates, therefore being the only synthetic antifungal that may potentially be used against Pneumocistis spp., Candida spp., and Cryptococcus spp.

MYC-053 was highly effective against preformed 48-h-old C. glabrata and C. neoformans biofilms, with the minimal biofilm eradication concentrations equal to 1–4 times MIC. Together, these data indicated that MYC-053 may be developed into a promising antifungal agent for the treatment and prevention of invasive fungal infections caused by yeasts and yeast-like fungi.

http://bit.ly/2TkEsP8

Y229W substitution in NDM-1/L209F variant restores the hydrolytic activity of the enzyme towards penicillins, cephalosporins and carbapenems: kinetic profile and molecular dynamic studies [Mechanisms of Resistance]

NDM-1 enzyme is the most common metallo-β-lactamase identified in many Gram-negative bacteria causing severe nosocomial infections. The aim of this study was to focus the attention on non-active site residues, L209 and Y229, of NDM-1 and to investigate their role in the catalytic mechanism. Specifically, the effect of Y229W substitution in L209F variant was evaluated by antimicrobial susceptibility testing, kinetic and molecular dynamic (MD) studies. The Y229W single mutant and L209F/Y229W double mutant were generated by site-directed mutagenesis. The K_m, k_cat and k_cat/K_m kinetic constants, calculated for the two mutants, were compared with those of NDM-1 and L209F variants. Compared to L209F single mutant, L209F/Y229W mutant showed a remarkable increase of k_cat values of 100-, 240-, 250- and 420-fold for imipenem, meropenem, benzylpenicillin and cefepime, respectively. In L209F/Y229W enzyme we observed a remarkable increase of k_cat/K_m of 370-, 140- and 80-fold for cefepime, meropenem and cefazolin, respectively. The same behavior was stated by antimicrobial susceptibility test. MD simulations were carried out on both L209F and L209F/Y229W enzymes complexed with benzylpenicillin focusing the attention on the overall mechanical features and on the differences between the two systems. With respect to L209F variant, the L209F/Y229W double mutant showed a mechanical stabilization of Loop 10 and N-terminal region but a destabilization of C-terminal and 149-154 regions. The epistatic effect of Y229W mutation jointly with stabilization of Loop 10 lead to a better catalytic efficiency of β-lactams. NDM numbering is used in order to facilitate the comparison with other NDM-1 studies.

http://bit.ly/2BbaMwL

Predicting Antibiotic Resistance in Gram-negative Bacilli from Resistance Genes [Mechanisms of Resistance]

We developed a rapid high throughput polymerase chain reaction (PCR) test and evaluated highly antibiotic-resistant clinical isolates of Escherichia coli (n=2919), Klebsiella pneumoniae (1974), Proteus mirabilis (1150) and Pseudomonas aeruginosa (1484) for several antibiotic resistance genes for comparison with phenotypic resistance across penicillins, cephalosporins, carbapenems, aminoglycosides, trimethoprim-sulfamethoxazole, fluoroquinolones and macrolides. The isolates originated from hospitals in North America (34%), Europe (23%), Asia (13%), South America (12%), Africa (7%), Oceania (1%) or unknown (9%). We developed statistical methods to predict phenotypic resistance from resistance genes for 49 antibiotic/organism combinations, including gentamicin, tobramycin, ciprofloxacin, levofloxacin, trimethoprim/sulfamethoxazole, ertapenem, imipenem, cefazolin, cefepime, cefotaxime, ceftazidime, ceftriaxone, ampicillin and aztreonam. Average positive predictive values for genotypic prediction of phenotypic resistance was E. coli (91%), K. pneumoniae (93%), P. mirabilis (87%) and P. aeruginosa (92%) across the various antibiotics for this highly resistant cohort of bacterial isolates.

http://bit.ly/2TfowxG