The mammalian target of rapamycin inhibitor RAD001 (everolimus) in early breast cancer

The mammalian target of rapamycin (mTOR) plays a key role in tumour cell cycle control, proliferation and survival, and has been implicated in resistance to endocrine therapy in breast cancer. RAD001 (everolimus) is a novel macrolide that inhibits mTOR and its downstream substrates in vitro. This study explores the use of RAD001 at a dose of 5mg daily in women with early breast cancer. 31 postmenopausal women were given RAD001 for 14 days prior to primary surgical intervention for early breast cancer. RAD001 was well tolerated in most patients, 5 did not complete treatment due to drug adverse effects. Tumour samples before (pre) and after (post) 14 days treatment were assessed for changes in proliferation and markers of the mTOR pathway. Significant reductions in proliferation (Ki67) and oestrogen receptor (ER) expression were seen, and the downstream effects of the mTOR pathway inhibited (p-S6 (ser235/236 and ser 240/244) and nuclear expression of p-Akt). Gene expression profiling from these tumour samples has confirmed these findings, demonstrating reduction in expression of proliferative genes and oestrogen dependence genes with RAD001 treatment. The mTOR protein exists in two distinct complexes, raptor and rictor, and it has previously been thought that mTOR inhibitors such as RAD001 only have effects upon raptor. The implication of this if correct would be upregulation of Akt (Protein Kinase B), which has been shown to be present in more aggressive and resistant tumour types. The cell line study described herein has demonstrated no upregulation in p-Akt expression with RAD001 treatment, and in one cell line inhibition of p-Akt was sustained with prolonged cell treatment

Quantification of Nitro-toxins in Karaka (Corynocarpus laevigatus) Drupes

The karaka (Corynocarpus laevigatus) is a tree native to New Zealand (NZ), found throughout the North and South Islands. Traditionally, many parts of the karaka were used by Māori, however the parts of the karaka of most interest are the berry and nut as they were valuable food sources, in particular the nut. Karaka was known to be a toxin-bearing food, however implementation of a traditional baking and soaking process meant that the nuts were left in states fit for consumption, more often than not. The nuts also had the benefit of being able to be stored for future use when other food sources were short in supply. Karaka was readily consumed up until the 1950s, after this consumption rates decreased rapidly, after the toxic effects were associated with the incorrect preparation of the nuts. Studies on karaka have revealed that the toxicity of the nuts primarily arises from various nitropropanoyl glucopyranoses (NPGs), twelve of which have been detected in karaka. The quantity of these NPGs has been infrequently studied and it is often only one of the NPGs-karakin which is quantified, although it is believed the toxicity in nuts arises collectively from all of the NPGs. As a result, there is the need to be able to quantify the NPGs in karaka and look at potential toxin removal techniques. If toxin removal can be accomplished, there is the potential for karaka to be a marketable ‘traditional’ or ‘Kiwi’ food item. Additionally, the toxins removed as a by-product may prove to have their own potential commercial applications, for example as insecticides or repellents. Since all the NPGs are assumed to be toxic, a method was developed to quantify the total toxicity in the nuts. The method involves the release of NPA via acid hydrolysis of the nitropropanoyl ester groups of the NPGs. The NPA is then able to be measured and subsequently quantified using HPLC. The method incorporates a correction factor (CF) that was determined to give the original NPA content at a time of zero (NPA0), accounting for the unavoidable loss of NPA that arises from the hydrolysis method. The average quantity of NPA in karaka nuts was found to range from 50.25 to 138.62 g kg-1 (dry weight) which is equivalent to 5.0 to 13.9%. These are much higher percentages than any previously reported because the method used in this study measured total NPA. Earlier methods measured a limited range of NPGs (often a single NPG) unhydrolysed and could have missed NPA arising from other compounds that contribute to total toxicity. Additionally, the concentrations of NPA in karaka nuts were influenced by a number of factors including intra and inter tree variation, storage conditions and ripeness. Although quantification was focused on determining NPA content in nuts, a test conducted also showed NPA to be present in increasingly lower levels in the berry flesh, shell and pellicle respectively. Nuts were subjected to various potential industrial processing techniques, treatment times and conditions, in order to determine their efficacy for toxin removal. Treatments included boiling, microwave cooking, soxhlet extraction, oven roasting, autoclaving and cold-water treatments. The efficiency of each treatment varied considerably, with both heat and water proving to be beneficial in toxin removal. However, treatments involving water were found to be more effective than heat treatments alone. Out of all treatment types, times and conditions tested, none were found to leave nuts with a NPA concentration lower than the estimated safe level of daily consumption for a 70 kg adult (< 1.75 mg). Additionally, only some of the treatments resulted in nuts being left in visually appealing states. At present, toxin removal by a single process in order to render karaka nuts safe to consume appears to be an impractical activity. However, if treatment protocols were combined and modified, there is the potential for the development of an effective detoxification process. Furthermore, tests on the treatment solutions revealed that NPA can be obtained in solution as a by-product of nut treatment; with cold-water proving to be more effective than treatments that also used heat. Obtaining NPA as a by-product of toxin removal in nuts appears to be a feasible option for a natural source of NPA

Letter on “Sharing trial results directly with trial participants and other stakeholders after the SARS-CoV-2 pandemic hit the UK:experience from the ActWELL trial

Acknowledgements We would like to thank our ActWELL participants who attended the events for their interest and enthusiasm in making the events a success. We would like to thank Susan MacAskill for giving us permission to use a quote from her email to us. We are also grateful to the technical support who got us through all events, Cormac Staunton (of stauntonmedia.ie). We would also like to acknowledge and thank Dr Katie Gillies and Dr Seonaidh Cotton for their contribution to the design of the evaluation survey. HSRU is core funded by the Chief Scientist Office of the Scottish Government Health and Social Care Directorates. This work was supported by The Scottish Government, grant number BC/ Screening/17/01.Peer reviewedPublisher PD

The value of prognostic ultrasound features of breast cancer in different molecular subtypes with a focus on triple negative disease

The ultrasound (US) features of breast cancer have recently been shown to have prognostic significance. We aim to assess these features according to molecular subtype. 1140 consecutive US visible invasive breast cancers had US size and mean stiffness by shearwave elastography (SWE) recorded prospectively. Skin thickening (> 2.5 mm) overlying the cancer on US and the presence of posterior echo enhancement were assessed retrospectively while blinded to outcomes. Cancers were classified as luminal, triple negative (TN) or HER2 + ve based on immunohistochemistry and florescent in-situ hybridization. The relationship between US parameters and breast cancer specific survival (BCSS) was ascertained using Kaplan–Meier survival curves and ROC analysis. At median follow-up 6.3 year, there were 117 breast cancer (10%) and 132 non-breast deaths (12%). US size was significantly associated with BCSS all groups (area under the curve (AUC) 0.74 in luminal cancers, 0.64 for TN and 0.65 for HER2 + ve cancers). US skin thickening was associated most strongly with poor prognosis in TN cancers (53% vs. 80% 6 year survival, p = 0.0004). Posterior echo enhancement was associated with a poor BCSS in TN cancers (63% vs. 82% 6 year survival, p = 0.02). Mean stiffness at SWE was prognostic in the luminal and HER2 positive groups (AUC 0.69 and 0.63, respectively). In the subgroup of patients with TN cancers receiving neo-adjuvant chemotherapy posterior enhancement and skin thickening were not associated with response. US skin thickening is a poor prognostic indicator is all 3 subtypes studied, while posterior enhancement was associated with poor outcome in TN cancer

Prediction of Pathological Complete Response to Neoadjuvant Chemotherapy for Primary Breast Cancer Comparing Interim Ultrasound, Shear Wave Elastography and MRI

Abstract Background Prediction of pathological complete response (pCR) of primary breast cancer to neoadjuvant chemotherapy (NACT) may influence planned surgical approaches in the breast and axilla. The aim of this project is to assess the value of interim shear wave elastography (SWE), ultrasound (US) and magnetic resonance imaging (MRI) after 3 cycles in predicting pCR. Methods 64 patients receiving NACT had baseline and interim US, SWE and MRI examinations. The mean lesion stiffness at SWE, US and MRI diameter was measured at both time points. We compared four parameters with pCR status: a) Interim mean stiffness ≤ or &gt; 50 kPa; b) Percentage stiffness reduction; c) Percentage US diameter reduction and d) Interim MRI response using RECIST criteria. The Chi square test was used to assess significance. Results Interim stiffness of ≤ or &gt; 50 kPa gave the best prediction of pCR with pCR seen in 10 of 14 (71 %) cancers with an interim stiffness of ≤ 50 kPa, compared to 7 of 50 (14 %) of cancers with an interim stiffness of &gt; 50 kPa, (p &lt; 0.0001) (sensitivity 59 %, specificity 91 %, PPV 71 %, NPV 86 % and diagnostic accuracy 83 %). Percentage reduction in stiffness was the next best parameter (sensitivity 59 %, specificity 85 %, p &lt; 0.0004) followed by reduction in MRI diameter of &gt; 30 % (sensitivity 50 % and specificity 79 %, p = 0.03) and % reduction in US diameter (sensitivity 47 %, specificity 81 %, p = 0.03). Similar results were obtained from ROC analysis. Conclusion SWE stiffness of breast cancers after 3 cycles of NACT and changes in stiffness from baseline are strongly associated with pCR after 6 cycles.</jats:p