Discovery of ONO-8590580: A novel, potent and selective GABAA α5 negative allosteric modulator for the treatment of cognitive disorders.

The identification and SAR development of a series of negative allosteric modulators of the GABAA α5 receptor is described. This novel series of compounds was optimised to provide analogues with high GABAA α5 binding affinity, high α5 negative allosteric modulatory activity, good functional subtype selectivity and low microsomal turnover, culminating in identification of ONO-8590580.

Combination of acellular dermal matrix with a de-epithelialised dermal flap during skin-reducing mastectomy and immediate breast reconstruction.

Introduction Patients with large ptotic breasts undergoing immediate implant-based reconstruction often require skin-reducing mastectomy to optimise the aesthetic outcome. However, healing complications, especially at the resulting inverted T-junction, leading to wound dehiscence, infection, skin necrosis, implant exposure and failed reconstruction have been widely reported. We present an innovative approach for immediate implant-based reconstruction combining porcine- or bovine-derived acellular dermal matrices with a de-epithelialised dermal sling to protect and support the implant, while improving clinical outcomes in this challenging group of patients. Materials and methods Demographic, tumour and surgical data were reviewed for patients undergoing Wise pattern (T-scar) skin-reducing mastectomies with immediate implant-based reconstruction combining porcine- or bovine-derived acellular dermal matrices with a de-epithelialised dermal sling. Results This technique was successfully employed to reconstruct five large pendulous breasts in four breast cancer patients with a median age of 50.5 years (range 34-61 years) who were not suitable for, or had declined, flap-based reconstruction. The acellular dermal matrices used were SurgiMend®, StratticeTM and Braxon® and the expandable implants were placed in the sub-pectoral (n = 3) and pre-pectoral (n = 1) planes. The technical steps and clinical outcomes are presented. One patient experienced T-junction breakdown overlying the de-epithelialised dermis without implant loss. Conclusion The combination of an acellular dermal matrix and a dermal sling provides a double-layer 'water-proofing' and support for the implants inferiorly, avoiding T-junction breakdown complications, since any dehiscence is on to well-vascularised dermis. Furthermore, the acellular dermal matrix stabilises the implant in the large mastectomy cavity (pocket control). This approach provides a viable option which facilitates mastectomy and immediate implant reconstruction in large-breasted patients.

An evaluation of the prognostic model PREDICT using the POSH cohort of women aged ⩽40 years at breast cancer diagnosis.

BACKGROUND: Breast cancer is the most common cancer in younger women (aged ⩽40 years) in the United Kingdom. PREDICT (http://www.predict.nhs.uk) is an online prognostic tool developed to help determine the best available treatment and outcome for early breast cancer. This study was conducted to establish how well PREDICT performs in estimating survival in a large cohort of younger women recruited to the UK POSH study. METHODS: The POSH cohort includes data from 3000 women aged ⩽40 years at breast cancer diagnosis. Study end points were overall and breast cancer-specific survival at 5, 8, and 10 years. Evaluation of PREDICT included model discrimination and comparison of the number of predicted versus observed events. RESULTS: PREDICT provided accurate long-term (8- and 10-year) survival estimates for younger women. Five-year estimates were less accurate, with the tool overestimating survival by 25% overall, and by 56% for patients with oestrogen receptor (ER)-positive tumours. PREDICT underestimated survival at 5 years among patients with ER-negative tumours. CONCLUSIONS: PREDICT is a useful tool for providing reliable long-term (10-year) survival estimates for younger patients. However, for more accurate short-term estimates, the model requires further calibration using more data from young onset cases. Short-term prediction may be most relevant for the increasing number of women considering risk-reducing bilateral mastectomy.

M1 and m2 muscarinic receptor subtypes regulate antidepressant-like effects of the rapidly acting antidepressant scopolamine.

Scopolamine produces rapid and significant symptom improvement in patients with depression, and most notably in patients who do not respond to current antidepressant treatments. Scopolamine is a nonselective muscarinic acetylcholine receptor antagonist, and it is not known which one or more of the five receptor subtypes in the muscarinic family are mediating these therapeutic effects. We used the mouse forced-swim test, an antidepressant detecting assay, in wild-type and transgenic mice in which each muscarinic receptor subtype had been genetically deleted to define the relevant receptor subtypes. Only the M1 and M2 knockout (KO) mice had a blunted response to scopolamine in the forced-swim assay. In contrast, the effects of the tricyclic antidepressant imipramine were not significantly altered by gene deletion of any of the five muscarinic receptors. The muscarinic antagonists biperiden, pirenzepine, and VU0255035 (N-[3-oxo-3-[4-(4-pyridinyl)-1-piper azinyl]propyl]-2,1,3-benzothiadiazole-4-sulfonamide) with selectivity for M1 over M2 receptors also demonstrated activity in the forced-swim test, which was attenuated in M1 but not M2 receptor KO mice. An antagonist with selectivity of M2 over M1 receptors (SCH226206 [(2-amino-3-methyl-phenyl)-[4-[4-[[4-(3 chlorophenyl)sulfonylphenyl]methyl]-1-piperidyl]-1-piperidyl]methanone]) was also active in the forced-swim assay, and the effects were deleted in M2 (-/-) mice. Brain exposure and locomotor activity in the KO mice demonstrated that these behavioral effects of scopolamine are pharmacodynamic in nature. These data establish muscarinic M1 and M2 receptors as sufficient to generate behavioral effects consistent with an antidepressant phenotype and therefore as potential targets in the antidepressant effects of scopolamine.

Tumour bed clip localisation for targeted breast radiotherapy: compliance is proportional to trial-related research activity: tumour bed clip localisation in breast radiotherapy.

BACKGROUND: In breast cancer, with the increasing use of intensity-modulated radiotherapy (IMRT), the need for accurate tumour bed localisation is paramount. We determined current practice of clip usage in patients referred to a regional centre for radiotherapy following breast conserving surgery. We also investigated whether participation of surgical units in IMRT trials, where tumour bed clip use is emphasised, was associated with clip insertion. METHODS: A retrospective cohort study of consecutive CT planning images (n = 205), of breast cancer patients treated with radiotherapy following breast conserving surgery. Presence and number of clips; referring hospital and referring surgeon of the patient was recorded. This was correlated to previous participation of referring hospital to IMRT trials. RESULTS: Of 196 eligible patients, 126 (64%) had clips sited, of which 15 (12%) had two or fewer clips. Five referring hospitals were high recruiters (≥14 patients), and five hospitals were low/non-recruiters (≤1 patient) to IMRT trials. Of patients from low/non-recruiting centres, 29 of 43 (67%) had clips omitted, compared to 41 of 153 (27%) from high-recruiting centres (p < 0.001). Median number of clips used in centres recruiting high numbers of patients was four, compared to zero in low recruiting centres. Ten of 31 referring surgeons routinely omitted clips. CONCLUSION: Despite inclusion in national guidelines, clip insertion has not become routine in the UK in patients undergoing breast conserving surgery. However, hospitals involved in breast radiotherapy randomised controlled trials are more compliant with clip usage recommendations. Auditing of clip insertion should be considered as a quality control marker in breast surgery.

Patterns of metastatic spread in early breast cancer.

AIMS: The aim of this study was to prospectively investigate metastatic pathways of spread to lymph node versus bone marrow and identify biological characteristics that determine these patterns in early invasive breast cancer. PATIENTS AND METHODS: In all, 177 patients with early invasive breast cancer underwent surgical extirpation of the primary tumour with sentinel lymph node biopsy (SLNB). Bone marrow (BM) aspiration was performed to screen for cytokeratin-positive cells by immunocytochemistry. Lymphatic spread was assessed by histopathological examination of lymph nodes (LN). A representative subset of 87 tumours was analysed by tissue microarray (TMA) to evaluate expression of markers that potentially influence haematogenous vs. lymphatic spread. Patients were followed up for a median of 54.7 months. RESULTS: Of the 177 patients, 114 (64%) were BM-/LN-, 38 (22%) BM-/LN+, 19 (11%) BM+/LN- and 6 (3%) BM+/LN+. Multivariate analysis of histopathological characteristics revealed that increasing tumour size was significantly associated with both LN positivity (p = 0.003) and BM positivity (p = 0.01), the presence of lymphovascular invasion significantly correlated with LN+ (p = 0.01), whereas lower histological grade was significantly associated with BM+ (p = 0.03). LN+ and BM+ were non-significantly negatively related to each other. Univariate analysis of the TMA data showed differential expression patterns for several factors; significant differences between effects on the two metastatic pathways (lymphatic vs. haematogenous) were found for expression of CD54 (p = 0.03), osteopontin (p = 0.04), bone sialoprotein (p = 0.04) and CXCR4 (p = 0.009). High expression of CD54, osteopontin and bone sialoprotein (BSP) was positively associated with BM + but was either not associated, or negatively associated, with LN+. High CXCR4 expression was positively associated with LN+ and negatively with BM+. High VEGF-C expression was associated with both LN+ and BM+, although this did not attain statistical significance. Due to the small number of clinical events during clinical follow-up, no associations were identified between metastatic spread patterns, recurrence and/or death. CONCLUSION: These findings suggest that distinct lymphatic and haematogenous metastatic pathways exist in early breast cancer and that these pathways are governed by specific biological markers.

Results of a national training programme in sentinel lymph node biopsy for breast cancer.

BACKGROUND: New Start, a structured, validated, multidisciplinary training programme in sentinel lymph node biopsy (SLNB), was established to allow the introduction and rapid transfer of appropriate knowledge and technical skills to ensure safe and competent practice across the UK. METHODS: Multidisciplinary teams attended a theory/skills laboratory course, following which they performed 30 consecutive SLNBs, either concurrently with their standard axillary staging procedure (training model A) or as stand-alone SLNB (training model B). SLNB was performed according to a standard protocol using the combined technique of isotope ((99m) Tc-labelled albumin colloid) and blue dye. An accredited New Start trainer mentored the first five procedures in the participant's hospital, or all 30 if stand-alone. Validation standards for model A and B were a localization rate of at least 90 per cent. In addition, for model A only, in which a minimum of ten patients were required to be node-positive, a false-negative rate (FNR) of 10 per cent or less was required. RESULTS: From October 2004 to December 2008, 210 SLNB-naive surgeons, in 103 centres, performed 6685 SLNB procedures. The overall sentinel lymph node (SLN) localization rate was 98·9 (95 per cent confidence interval 98·6 to 99·1) per cent (6610 of 6685) and the FNR 9·1 (7·9 to 10·5) per cent (160 of 1757). The FNR was related to nodal yield, ranging from 14·8 per cent for one node and declining to 9·7, 6·6, 4·7 and 4·1 per cent for two, three, four and more than four SLNs respectively. No learning curve was identified for localization or FNR. CONCLUSION: The programme successfully trained a wide range of UK breast teams to perform safe SLNB and suggested that a standard injection protocol and structured multidisciplinary training can abolish learning curves.

PREDICT Plus: development and validation of a prognostic model for early breast cancer that includes HER2.

BACKGROUND: Predict (www.predict.nhs.uk) is an online, breast cancer prognostication and treatment benefit tool. The aim of this study was to incorporate the prognostic effect of HER2 status in a new version (Predict+), and to compare its performance with the original Predict and Adjuvant!. METHODS: The prognostic effect of HER2 status was based on an analysis of data from 10 179 breast cancer patients from 14 studies in the Breast Cancer Association Consortium. The hazard ratio estimates were incorporated into Predict. The validation study was based on 1653 patients with early-stage invasive breast cancer identified from the British Columbia Breast Cancer Outcomes Unit. Predicted overall survival (OS) and breast cancer-specific survival (BCSS) for Predict+, Predict and Adjuvant! were compared with observed outcomes. RESULTS: All three models performed well for both OS and BCSS. Both Predict models provided better BCSS estimates than Adjuvant!. In the subset of patients with HER2-positive tumours, Predict+ performed substantially better than the other two models for both OS and BCSS. CONCLUSION: Predict+ is the first clinical breast cancer prognostication tool that includes tumour HER2 status. Use of the model might lead to more accurate absolute treatment benefit predictions for individual patients.

A feasibility study (ICG-10) of indocyanine green (ICG) fluorescence mapping for sentinel lymph node detection in early breast cancer.

BACKGROUND: There is now increasing evidence to support the use of indocyanine green (ICG) for sentinel lymph node (SLN) detection in early breast cancer. The primary objective of this feasibility study (ICG-10) was to determine the sensitivity and safety of ICG fluorescence imaging in sentinel lymph node identification when combined with blue dye and radiocolloid. METHODS: One hundred women with clinically node negative breast cancer (95 unilateral; 5 bilateral) had sentinel lymph node (SLN) biopsy using blue dye, radioisotope and ICG. One patient was excluded from analysis and sensitivity, or detection rate, of ICG alone, and in combination with blue dye and/or radioisotope, was calculated for the remaining 104 procedures in 99 patients. RESULTS: Transcutaneous fluorescent lymphography was visible in all 104 procedures. All 202 true SLNs, defined as blue and/or radioactive, were also fluorescent with ICG. Detection rates were: ICG alone 100%, ICG & blue dye 95.0%, ICG & radioisotope 77.2%, ICG & blue dye & radioisotope 73.1%. Metastases were found in 25 of 201 SLNs (12.4%) and all positive nodes were fluorescent, blue and radioactive. The procedural node positivity rate was 17.3%. CONCLUSION: The results of this study confirm the high sensitivity of ICG fluorescence for SLN detection in early breast cancer. The combination of ICG and blue dye had the highest nodal sensitivity at 95.0% defining a dual approach to SLN biopsy that avoids the need for radioisotope.

Association of breast tumour bed seroma with post-operative complications and late normal tissue toxicity: results from the Cambridge Breast IMRT trial.

AIMS: There are two main surgical techniques for managing the tumour bed after breast cancer excision. Firstly, closing the defect by suturing the cavity walls together and secondly leaving the tumour bed open thus allowing seroma fluid to collect. There is debate regarding which technique is preferable, as it has been reported that a post-operative seroma increase post-operative infection rates and late normal tissue side effects. METHODS: Data from 648 patients who participated in the Cambridge Breast IMRT trial were used. Seromas were identified on axial CT images at the time of radiotherapy planning and graded as not visible/subtle or easily visible. An association was sought between the presence of seroma and the development of post-operative infection, post-operative haematoma and 2 and 5 years normal tissue toxicity (assessed using serial photographs, clinical assessment and self assessment questionnaire). RESULTS: The presence of easily visible seroma was associated with increased risk of post-operative infection (OR = 1.80; p = 0.004) and post-operative haematoma (OR = 2.1; p = 0.02). Breast seroma was an independent risk factor for whole breast induration and tumour bed induration at 2 and 5 years. The presence of breast seroma was also associated with inferior overall cosmesis at 5 years. There was no significant association between the presence of seroma and the development of either breast shrinkage or breast pain. CONCLUSION: The presence of seroma at the time of radiotherapy planning is associated with increased rates of post-operative infection and haematoma. It is also an independent risk factor for late normal tissue toxicity. This study suggests that full thickness surgical closure may be desirable for patients undergoing breast conservation and radiotherapy.