Evaluation of tumour hypoxia during radiotherapy using [<Superscript>18</Superscript>F]HX4 PET imaging and blood biomarkers in patients with head and neck cancer

Background and purpose

Increased tumour hypoxia is associated with a worse overall survival in patients with head and neck squamous cell carcinoma (HNSCC). The aims of this study were to evaluate treatment-associated changes in [¹⁸F]HX4-PET, hypoxia-related blood biomarkers, and their interdependence.

Material and methods

[¹⁸F]HX4-PET/CT scans of 20 patients with HNSCC were acquired at baseline and after ±20Gy of radiotherapy. Within the gross-tumour-volumes (GTV; primary and lymph nodes), mean and maximum standardized uptake values, the hypoxic fraction (HF) and volume (HV) were calculated. Also, the changes in spatial uptake pattern were evaluated using [¹⁸F]HX4-PET/CT imaging. For all patients, the plasma concentration of CAIX, osteopontin and VEGF was assessed.

Results

At baseline, tumour hypoxia was detected in 69 % (22/32) of the GTVs. During therapy, we observed a significant decrease in all image parameters. The HF decreased from 21.7?±?19.8 % (baseline) to 3.6?±?10.0 % (during treatment; P?<?0.001). Only two patients had a HV?>?1 cm³ during treatment, which was located for >98 % within the baseline HV. During treatment, no significant changes in plasma CAIX or VEGF were observed, while osteopontin was increased.

Conclusions

[¹⁸F]HX4-PET/CT imaging allows monitoring changes in hypoxia during (chemo)radiotherapy whereas the blood biomarkers were not able to detect a treatment-associated decrease in hypoxia.

     

Subacute haematotoxicity after PRRT with <Superscript>177</Superscript>Lu-DOTA-octreotate: prognostic factors,incidence and course

Purpose

In peptide receptor radionuclide therapy (PRRT), the bone marrow (BM) is one of the dose-limiting organs. The accepted dose limit for BM is 2 Gy, adopted from ¹³¹I treatment. We investigated the incidence and duration of haematological toxicity and its risk factors in patients treated with PRRT with ¹⁷⁷Lu-DOTA⁰-Tyr³-octreotate (¹⁷⁷Lu-DOTATATE). Also, absorbed BM dose estimates were evaluated and compared with the accepted 2 Gy dose limit.

Methods

The incidence and duration of grade 3 or 4 haematological toxicity (according to CTCAE v3.0) and risk factors were analysed. Mean BM dose per unit (gigabecquerels) of administered radioactivity was calculated and the correlations between doses to the BM and haematological risk factors were determined.

Results

Haematological toxicity (grade 3/4) occurred in 34 (11 %) of 320 patients. In 15 of the 34 patients, this lasted more than 6 months or blood transfusions were required. Risk factors significantly associated with haematological toxicity were: poor renal function, white blood cell (WBC) count <4.0?×?10⁹/l, age over 70 years, extensive tumour mass and high tumour uptake on the OctreoScan. Previous chemotherapy was not associated. The mean BM dose per administered activity in 23 evaluable patients was 67?±?7 mGy/GBq, resulting in a mean BM dose of 2 Gy in patients who received four cycles of 7.4 GBq ¹⁷⁷Lu-DOTATATE. Significant correlations between (cumulative) BM dose and platelet and WBC counts were found in a selected group of patients.

Conclusion

The incidence of subacute haematological toxicity after PRRT with ¹⁷⁷Lu-DOTATATE is acceptable (11 %). Patients with impaired renal function, low WBC count, extensive tumour mass, high tumour uptake on the OctreoScan and/or advanced age are more likely to develop grade 3/4 haematological toxicity. The BM dose limit of 2 Gy, adopted from ¹³¹I, seems not to be valid for PRRT with ¹⁷⁷Lu-DOTATATE.

     

MRI characteristics of proctitis in Crohn’s disease on perianal MRI

Purpose

Multiple features have been described for assessing inflammation in Crohn’s disease (CD) in MR enterography, but have not been validated in perianal magnetic resonance imaging (MRI). Retrospectively, we studied which MRI features are valuable in assessing proctitis.

Materials and methods

CD patients (≥18 years) who underwent colonoscopy (reference standard) and perianal fistula MRI within 8 weeks were included. Seventeen MRI features were blindly scored by three observers and correlated to endoscopy (regression analysis). Reproducibility (multirater kappa, intraclass correlation coefficient) was determined for all three observer pairs. MRI features were considered relevant when significantly correlated to endoscopy for ≥2 observers, and reproducibility was ≥0.40 for ≥2 observer pairs.

Results

Perianal MRI of 58 CD patients were included. Wall thickness, rectal mural fat, creeping fat, and size of mesorectal lymph nodes showed a significant correlation with endoscopy for ≥2 observers (p = 0.000–0.023, p = 0.011–0.172, p = 0.007–0.011 and p = 0.000–0.005, respectively) with a kappa/intraclass correlation coefficient of ≥0.60 for ≥2 observer pairs. Perimural T2 signal and perimural enhancement significantly correlated to endoscopy (all p values ≤0.05) for all three observers and the reproducibility was ≥0.40 for ≥2 observer pairs. Mural T2 signal and degree and pattern of T1 enhancement showed significant correlation to endoscopy for two observers, but with poor to moderate reproducibility.

Conclusion

Wall thickness, mural fat, and mesorectal features (perimural T2 signal, perimural enhancement, creeping fat, and size of mesorectal lymph nodes) had significant correlation to endoscopy and were reproducible in diagnosing proctitis. Some established luminal features in MRE were considered not useful.

     

Priming with an adenovirus 35-circumsporozoite protein (CS) vaccine followed by RTS,S/AS01B boosting significantly improves immunogenicity to Plasmodium falciparum CS compared to that with either malaria vaccine alone

The RTS,S/AS02A protein-based vaccine consistently demonstrates significant protection against infection with Plasmodium falciparum malaria and also against clinical malaria and severe disease in children in areas of endemicity. Here we demonstrate with rhesus macaques that priming with a replication-defective human adenovirus serotype 35 (Ad35) vector encoding circumsporozoite protein (CS) (Ad35.CS), followed by boosting with RTS,S in an improved MPL- and QS21-based adjuvant formulation, AS01B, maintains antibody responses and dramatically increases levels of T cells producing gamma interferon and other Th1 cytokines in response to CS peptides. The increased T-cell responses induced by the combination of Ad35.CS and RTS,S/AS01B are sustained for at least 6 months postvaccination and may translate to improved and more durable protection against P. falciparum infection in humans.     

TDP-43 in familial and sporadic frontotemporal lobar degeneration with ubiquitin inclusions

TAR DNA-binding protein 43 (TDP-43) is a major pathological protein of sporadic and familial frontotemporal lobar degeneration with ubiquitin-positive, tau-negative inclusions (FTLD-U) with or without motor neuron disease (MND). Thus, TDP-43 defines a novel class of neurodegenerative diseases called TDP-43 proteinopathies. We performed ubiquitin and TDP-43 immunohistochemistry on 193 cases of familial and sporadic FTLD with or without MND. On selected cases, immunoelectron microscopy and biochemistry were performed. Clinically defined frontotemporal dementias (FTDs) included four groups: 1) familial FTD with mutations in progranulin (n = 36), valosin-containing protein (n = 5), charged multivesicular body protein 2B (n = 4), and linked to chromosome 9p (n = 7); 2) familial cases of FTD with unknown gene association (n = 29); 3) sporadic FTD (n = 72); and 4) familial and sporadic FTD with MND (n = 40). Our studies confirm that the spectrum of TDP-43 proteinopathies includes most cases of sporadic and familial FTLD-U with and without MND and expand this disease spectrum to include reported families with FTD linked to chromosome 9p but not FTD with charged multivesicular body protein 2B mutations. Thus, despite significant clinical, genetic, and neuropathological heterogeneity of FTLD-U, TDP-43 is a common pathological substrate underlying a large subset of these disorders, thereby implicating TDP-43 in novel and unifying mechanisms of FTLD pathogenesis.     

Nurses’ perceptions towards the delivery and feasibility of a behaviour change intervention to enhance physical activity in patients at risk for cardiovascular disease in primary care: a qualitative study

Background

Self-management support is widely accepted for the management of chronic conditions. Self-management often requires behaviour change in patients, in which primary care nurses play a pivotal role. To support patients in changing their behaviour, the structured behaviour change Activate intervention was developed. This intervention aims to enhance physical activity in patients at risk for cardiovascular disease in primary care as well as to enhance nurses’ role in supporting these patients. This study aimed to evaluate nurses’ perceptions towards the delivery and feasibility of the Activate intervention.

Methods

A qualitative study nested within a cluster-randomised controlled trial using semistructured interviews was conducted and thematically analysed. Fourteen nurses who delivered the Activate intervention participated.

Results

Three key themes emerged concerning nurses’ perceptions of delivering the intervention: nurses’ engagement towards delivering the intervention; acquiring knowledge and skills; and dealing with adherence to the consultation structure. Three key themes were identified concerning the feasibility of the intervention: expectations towards the use of the intervention in routine practice; perceptions towards the feasibility of the training programme; and enabling personal development.

Conclusions

Delivering a behaviour change intervention is challenged by the complexity of changing nurses’ consultation style, including acquiring corresponding knowledge and skills. The findings have increased the understanding of the effectiveness of the Activate trial and will guide the development and evaluation of future behaviour change interventions delivered by nurses in primary care.

Trial registration

ClinicalTrials.gov NCT02725203.

     

Rapid screening test for primary hyperaldosteronism: ratio of plasma aldosterone to renin concentration determined by fully automated chemiluminescence immunoassays

BACKGROUND: The ratio of plasma aldosterone concentration to plasma renin activity (PAC/PRA) is the most common screening test for primary hyperaldosteronism (PHA), but it is not standardized among laboratories. We evaluated new automated assays for the simultaneous measurement of PAC and plasma renin concentration (PRC). METHODS: We studied 76 healthy normotensive volunteers and 28 patients with confirmed PHA. PAC and PRC were measured immunochemically in EDTA plasma on the Nichols Advantage chemiluminescence analyzer, and PRA was determined by an activity assay. RESULTS: In volunteers, PAC varied from 33.3 to 1930 pmol/L, PRA from 1.13 to 19.7 ng.mL(-1).h(-1) (0.215 ng.mL(-1).h(-1) = 1 pmol.L(-1).s(-1)), and PRC from 5.70 to 116 mU/L. PAC/PRA ratios ranged from 4.35 to 494 (pmol/L)/(ng.mL(-1).h(-1)) and PAC/PRC ratios from 0.69 to 71.0 pmol/mU. In PHA patients, PAC ranged from 158 to 5012 pmol/L, PRA from 0.40 to 1.70 ng.mL(-1).h(-1), and PRC from 0.80 to 11.7 mU/L. PAC/PRA ratios were between 298 and 6756 (pmol/L)/(ng.mL(-1).h(-1)) and PAC/PRC ratios between 105 and 2328 pmol/mU. Whereas PAC or PRC showed broad overlap between PHA patients and volunteers, the PAC/PRC ratio indicated distinct discrimination of these two groups at a cutoff of 71 pmol/mU. CONCLUSION: The PAC/PRC ratio offers several practical advantages compared with the PAC/PRA screening method. The present study offers preliminary evidence that it may be a useful screening test for PHA. Further studies are required to validate these results, especially in hypertensive cohorts.