Surgical Training Simulators for Rhinoplasty: A Systematic Review.

Rhinoplasty training currently follows an apprenticeship model that is largely observational. Trainees have limited experience in performing maneuvers of this complex surgery. Rhinoplasty simulators can address this issue by providing trainees with the opportunity to gain surgical simulator experience that could improve technical competences in the operating room. This review amalgamates the collective understanding of rhinoplasty simulators described to date. In accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines, PubMed, OVID Embase, OVID Medline, and Web of Science databases were all searched for original research on surgical simulators for rhinoplasty education and reviewed by independent reviewers. Articles underwent title and abstract screening, and then relevant articles underwent full-text review to extract simulator data. Seventeen studies, published between 1984 and 2021, were included for final analysis. Study participant numbers ranged from 4 to 24, and included staff surgeons, fellows, residents (postgraduate year 1-6), and medical students. Cadaveric surgical simulators comprised eight studies, of which three were with human cadavers, one study was a live animal simulator, two were virtual simulators, and six were three-dimensional (3D) models. Both animal and human-based simulators increased the confidence of trainees significantly. Significant improvement in various aspects of rhinoplasty knowledge occurred with implementation of a 3D-printed model in rhinoplasty education. Rhinoplasty simulators are limited by a lack of an automated method of evaluation and a large reliance on feedback from experienced rhinoplasty surgeons. Rhinoplasty simulators have the potential to provide trainees with the opportunity for hands-on training to improve skill and develop competencies without putting patients in harm's way. Current literature on rhinoplasty simulators largely focuses on simulator development, with few simulators being validated and assessed for utility. For wider implementation and acceptance, further refinement of simulators, validation, and assessment of outcomes is required.

Long-Term Bonding Efficacy of CAD/CAM Hybrid Restorative Materials and Universal Adhesives.

OBJECTIVES: In-office and lab milled prostheses are the staple for indirect restorations. It is therefore critical to determine their long-term bonding durability. METHODS: CAD/ CAM blocks of two classes of restorative materials: 1) a nano-ceramic reinforced polymer matrix (NCPM) and, 2) a polymer-infiltrated ceramic network (PICN) were bonded using four different universal adhesives (UA) and silane systems. A lithium disilicate glassceramic (LDS) was used as a reference. The blocks were bisected and bonded with different UA/resin-cement pairs. Bonded blocks were then cut into 1.0x1.0x12.0 mm bar specimens for microtensile bond testing. Half the bars were subjected to bond strength testing immediately and the other half after aging by 50,000 thermal cycles between 5°C and 55°C. ANOVA and post-hoc tests were used to compare mean bond strength among groups. RESULTS: NCPM presented consistently high bond strength regardless of bonding techniques, while the bond strength of PICN and LDS were lower when bonded with UA relative to traditional silanes. The more hydrophilic UA produced higher bond strengths. DISCUSSION: Glass-ceramics exhibited lower bond strength with UA than the conventional etch-rinse-silane techniques. However, UAs preserved bonding interface in the long-term. SIGNIFICANCE: NCPM displayed superior bond strength relative to PICN and LDS regardless of the type of adhesives and bonding techniques.

Diagnosis of osteoarticular tuberculosis by immuno-PCR assay based on mycobacterial antigen 85 complex detection.

Diagnosis of osteoarticular tuberculosis (OATB) exhibits serious challenges owing to paucibacillary nature of specimens and localization of disease at sites that are difficult to access. We recently developed indirect immuno-PCR (I-PCR) and real-time I-PCR (RT-I-PCR) assays for the detection of mycobacterial antigen 85 complex (Ag85) in OATB patients. Detection limits for the purified Ag85 protein were found to be 1 and 41 fg ml-1 by I-PCR and RT-I-PCR, respectively, which were at least 105 -fold lower than respective ELISA. While spiking synovial fluids of non-TB control subjects with the purified Ag85 protein, LODs of 100 and 120 fg ml-1 were obtained by I-PCR and RT-I-PCR, respectively, thus demonstrating the sample matrix effect. Sensitivities of 87·5 and 70·5% were observed in bodily fluids of confirmed (n = 8) and clinically suspected (n = 51) OATB cases, respectively, by I-PCR, with a specificity of 93·9% (n = 33). Markedly, the sensitivities obtained by I-PCR/RT-I-PCR were significantly higher (P < 0·05-0·01) than ELISA and GeneXpert assay (n = 30). However, no substantial difference in sensitivity was observed between the I-PCR and RT-I-PCR assays. After further improving the accuracy of I-PCR, this test may lead to development of an attractive diagnostic kit.

FAN1 modifies Huntington's disease progression by stabilizing the expanded HTT CAG repeat.

Huntington's disease (HD) is an inherited neurodegenerative disease caused by an expanded CAG repeat in the huntingtin (HTT) gene. CAG repeat length explains around half of the variation in age at onset (AAO) but genetic variation elsewhere in the genome accounts for a significant proportion of the remainder. Genome-wide association studies have identified a bidirectional signal on chromosome 15, likely underlain by FANCD2- and FANCI-associated nuclease 1 (FAN1), a nuclease involved in DNA interstrand cross link repair. Here we show that increased FAN1 expression is significantly associated with delayed AAO and slower progression of HD, suggesting FAN1 is protective in the context of an expanded HTT CAG repeat. FAN1 overexpression in human cells reduces CAG repeat expansion in exogenously expressed mutant HTT exon 1, and in patient-derived stem cells and differentiated medium spiny neurons, FAN1 knockdown increases CAG repeat expansion. The stabilizing effects are FAN1 concentration and CAG repeat length-dependent. We show that FAN1 binds to the expanded HTT CAG repeat DNA and its nuclease activity is not required for protection against CAG repeat expansion. These data shed new mechanistic insights into how the genetic modifiers of HD act to alter disease progression and show that FAN1 affects somatic expansion of the CAG repeat through a nuclease-independent mechanism. This provides new avenues for therapeutic interventions in HD and potentially other triplet repeat disorders.

Association between Smoking Exposure, Neoadjuvant Chemotherapy Response and Survival Outcomes following Radical Cystectomy: Systematic Review and Meta-Analysis.

PURPOSE: Studies exploring the association of cigarette smoking and long-term survival outcomes following radical cystectomy have yielded mixed results. We performed a systematic review and meta-analysis to investigate the impact of tobacco smoking exposure, duration, intensity and cessation on response to neoadjuvant chemotherapy and long-term survival outcomes in patients undergoing radical cystectomy for bladder cancer. MATERIALS AND METHODS: We systematically searched PubMed®, MEDLINE®, Embase® and Cochrane® Library databases for original articles published before April 2019. Primary end points were neoadjuvant chemotherapy response, overall and cancer specific mortality, and recurrence-free survival after radical cystectomy. Observational studies reporting Cox proportional hazards regression or logistic regression analysis were independently screened. Available multivariable hazard ratios and corresponding 95% CIs were included in the quantitative analysis. Sensitivity analyses were performed as appropriate. A risk of bias assessment was completed for nonrandomized studies. RESULTS: Our electronic search identified a total of 649 articles. After a detailed review we selected 17 studies that addressed the impact of smoking status on survival outcomes in 13,777 patients after radical cystectomy for bladder cancer. Pooled meta-analysis revealed that active smokers have an increased risk of overall mortality (HR 1.21, 95% CI 1.08-1.36; p=0.001, I2=0%), cancer specific mortality (HR 1.24, 95% CI 1.13-1.36; p <0.00001, I2=0%) and bladder cancer recurrence (HR 1.24, 95% CI 1.12-1.38; p <0.0001, I2=3%). Sensitivity analyses evaluating only patients who underwent neoadjuvant chemotherapy followed by radical cystectomy showed an advantage of non/never smokers in terms of neoadjuvant chemotherapy complete response rate (HR 0.47, 95% CI 0.29-0.75; p=0.001, I2=0%). CONCLUSIONS: Smoking status is associated with lower neoadjuvant chemotherapy response rates and higher overall and cancer specific mortality as well as bladder cancer recurrence after radical cystectomy. Appropriate preoperative counseling, together with tightened followup, may have a pivotal role in improving the smoking-related long-term survival outcomes in patients with bladder cancer.

Understanding the holistic experiences of living with a kidney transplant: an interpretative phenomenological study (protocol).

BACKGROUND: Currently very little is known about the perceptions and experiences of kidney transplant recipients from a qualitative perspective. As highlighted by the European Kidney Health Alliance recommendations, providing holistic care to kidney patients is important however this is currently an unmet care need in renal disease. It is imperative to understand patient experiences to ensure that they are included in key strategies and future renal service planning. Ignoring these important patient views means that there is a significant risk of inappropriate renal service provision and lack of adequate support impacting on overall health. METHOD: A purposive sampling strategy will recruit individuals currently living with a kidney transplant, 6 months to 5 years post-transplant. A maximum of 30 patients will be recruited between two Regional Nephrology units within the United Kingdom via clinical gatekeepers. In-depth interviews will be undertaken with participants living with a kidney transplant across the two sites. Interviews will be digitally-recorded, transcribed verbatim and subjected to interpretative phenomenological analysis. DISCUSSION: Renal healthcare professionals need to understand more than the biological impact of receiving a kidney transplant. Understanding the holistic and multi-domain experiences that these patients experience will help healthcare professionals to recognize the needs of this group and ensure more responsive care.

Carbohydrate restriction for glycaemic control in Type 2 diabetes: a systematic review and meta-analysis.

AIM: To conduct a systematic review and meta-analysis to evaluate the effect of carbohydrate restriction on glycaemic control in Type 2 diabetes. METHODS: We searched Medline, EMBASE and CINAHL for the period between 1976 and April 2018. We included randomized controlled trials comparing carbohydrate restriction with a control diet which aimed to maintain or increase carbohydrate intake, and that reported HbA1c as an outcome and reported the amount of carbohydrate consumed during or at the end of the study, with outcomes reported at ≥3 months. RESULTS: We identified 1402 randomized controlled trials, 25 of which met the inclusion criteria, incorporating 2132 participants for the main outcome. Definitions of low carbohydrate varied among the studies. The pooled effect estimate from meta-analysis was a weighted mean difference of -0.09% [95% CI -0.27, 0.08 (P = 0.30); I2 72% (P <0.001)], suggesting no effect on HbA1c of restricting the quantity of carbohydrate. A subgroup analysis of diets containing 50-130 g carbohydrate resulted in a pooled effect estimate of -0.49% [95% CI -0.75, -0.23 (P <0.001); I2 0% (P = 0.56)], suggesting a clinically and statistically significant effect on HbA1c in favour of low-carbohydrate diets in studies of ≤6 months' duration. CONCLUSIONS: There was no overall pooled effect on HbA1c in favour of restricting carbohydrate; however, restriction of carbohydrate to 50-130 g per day had beneficial effects on HbA1c in trials up to 6 months. Future randomized controlled trials should be of >12 months' duration, assess pre-study carbohydrate intake, use recognized definitions of low-carbohydrate diets and examine reasons for non-adherence to prescribed diets in greater detail.

Chaos in a ring circuit.

A ring-shaped logic circuit is proposed here as a robust design for a True Random Number Generator (TRNG). Most existing TRNGs rely on physical noise as a source of randomness, where the underlying idealized deterministic system is simply oscillatory. The design proposed here is based on chaotic dynamics and therefore intrinsically displays random behavior, even in the ideal noise-free situation. The paper presents several mathematical models for the circuit having different levels of detail. They take the form of differential equations using steep sigmoid terms for the transfer functions of logic gates. A large part of the analysis is concerned with the hard step-function limit, leading to a model known in mathematical biology as a Glass network. In this framework, an underlying discrete structure (a state space diagram) is used to describe the likely structure of the global attractor for this system. The latter takes the form of intertwined periodic paths, along which trajectories alternate unpredictably. It is also invariant under the action of the cyclic group. A combination of analytical results and numerical investigations confirms the occurrence of symmetric chaos in this system, which when implemented in (noisy) hardware, should therefore serve as a robust TRNG.

Medical Malpractice Defense: The Predictive and Protective Power of Mortality, Survival, and Life Expectancy.

Introduction.-The defense of medical malpractice presents a significant challenge to Assistant United States Attorneys (AUSAs). A medical malpractice claim consists of proof of: (1) duty, (2) breach of the duty, (3) causation, and (4) damages. Often the breach of the duty and the causation elements present complex medical issues involving multiple specialties and subspecialties of medicine. A considerable amount of time is required to prepare the defense pertaining to the alleged breach of the duty and causation elements. The damages aspect of the medical malpractice case is often not given equal treatment and may not be fully developed. As a result, damage awards can be surprisingly high once the breach of the standard of care and the causation defenses fail. Purpose.-The purpose of this article is to underscore the importance of developing the damages aspect of the case. This article will demonstrate through a case study the power of using fact-based medical-actuarial risk statistics and life expectancy testimony to limit, by thousands if not millions of dollars, economic damages to impairment-specific "years of life lost" in medical-malpractice torts. The important points to remember are that from the moment a case is assigned to an AUSA, the AUSA must: (1) focus as much, if not more, attention on damages; (2) execute a discovery strategy that ensures all aspects of damages are thoroughly investigated; and (3) retain the appropriate experts, including, in appropriate cases, an expert on medical risk appraisal and life expectancy.

Effect of sodium benzoate application on quality and enzymatic changes of pear fruits during low temperature.

Effect of postharvest applications of sodium benzoate on physico-chemical properties and enzymatic activities of pear fruit cv. Patharnakh during cold storage were examined. Uniform and healthy fruits of pear cv. Patharnakh were treated with sodium benzoate (0.0, 1.0, 2.0 and 3.0%) and thereafter stored at low temperature conditions (0-1 °C and 90-95% RH) for 70 days. Evaluation of physico-chemical parameters and enzymatic activities were made at 0, 20, 40, 60 and 70 days of storage. Sodium benzoate treatments effectively retained higher fruit firmness, sensory quality, total phenolics content and alongside suppressed the degradation of total soluble solids, ascorbic acid content and titratable acidity. Sodium benzoate treated fruits also exhibited higher efficacy in maintaining less enzymatic activity of cellulase, pectin methyl esterase and polyohenol oxidase. It was inferred that the postharvest treatments of sodium benzoate proved to be an effective means of improving quality and postharvest life of 'Patharnakh' pear fruit.

Influence of pre-harvest sprays of calcium nitrate on storability and quality attributes of plum fruits.

The effects of pre-harvest applications of calcium nitrate at different concentrations were investigated on storability and quality attributes of plum fruits under low temperature storage. Uniform and healthy trees of plum cv. Satluj Purple were sprayed with calcium nitrate (1.0%, 1.5% and 2.0%) in 2nd and 3rd week of April and control trees were water sprayed only. Fruits from treated and control trees were harvested at colour break stage, and then stored at low temperature conditions (0-1 °C and 90-95% RH) for 35 days. Evaluation of physico-chemical parameters and enzymatic activities were made on the day of harvest and after 7, 14, 21, 28 and 35 days of storage. The colour of the fruits with respect to a* and b* values (green-red and blue-yellow spectrum, respectively) improved progressively up to 35 days of storage, whereas, fruit firmness decreased. Total sugars and pectin methylesterase (PME) and cellulase activities increased up to 28 days of storage before showing a declining trend. Two superimposed sprays of calcium nitrate (2.0%) enhanced the storage life of plum fruits up to 28 days by reducing physiological loss in weight (PLW), PME and cellulase activities, delaying development of fruit colour & anthocyanin and retaining sensory quality, firmness and total sugars in plum fruits.

Ripening quality of Dusehri mango in relation to harvest time.

The effect of different harvesting time on ripening quality of mango cv. Dusehri was investigated under sub-tropics of northwestern India. Fruits were harvested at 101, 106 and 111 days after fruit set (DAFS) and kept at 25 °C in temperature controlled chamber for ripening. Fruits were analyzed periodically for physico-chemical characteristics at the time of harvest (0 h) and after 72, 96 and 120 h of ripening period. With advancement in ripening period, an increase in physiological loss in weight, soluble solids content (SSC), sensory quality rating, ß-carotene and pulp colour development of mango fruits was recorded. While a decline in fruit firmness and titratable acidity (TA) was observed with ripening period. Fruits picked at 111 DAFS recorded highest SSC (8.01%), sensory rating (4.67), ß-carotene (0.427 mg/100 g) vis-à-vis lowest fruit firmness (15.3 lbf) and TA content (1.56%). The luminosity of fruit pulp decreased with the storage period. The redness and yellowness of the fruit pulp represented by a* and b* values, respectively increased with delay in harvesting period. The rate of ripening was rapid in late harvested fruits as compared to early harvested fruits. After 96 h of ripening period, fruits harvested at 111 DAFS showed very much desirable quality whereas fruits harvested at 101 DAFS showed moderately desirable quality. Results showed that harvesting of mango fruits can be extended to 111 days and such fruits attained optimum ripening quality after 96 h at 25 °C.

Contemporary indications for diagnostic open biopsy in women assessed for screen-detected breast lesions: A ten-year, single institution series of 814 consecutive cases.

PURPOSE: In contemporary practice, 5% of women with non-malignant needle biopsies of screen-detected lesions still require diagnostic open biopsy (OBx). Our aims are to (i) capture a snapshot of the contemporary indications for OBx in screen-detected lesions; (ii) determine upgrade rates to malignancy (DCIS or invasive cancer); (iii) identify indications with sufficiently low upgrades to justify avoidance of OBx and (iv) propose plausible non-surgical alternatives. METHODS: Between Jan 2005 and Dec 2014, women assessed for a screen-detected lesion and recommended for OBx are included. We retrieved patient, imaging, biopsy and final pathology or follow-up data. RESULTS: 814 lesions, mean diameter 16.7 mm, microcalcifications in 353 (43.4%) cases, lesions other than calcifications in 461 (56.6%), mean patient age 58.4 yrs, are included. Surgery was performed in 98.2% cases. Imaging follow-up (1-6.5 yrs) is available in 13 of 15 remaining cases. 27 indications for OBx were identified, with a prevalence of 0.3-13.9%. Borderline lesions (BL) comprised 64% of OBx indications, amongst which atypical ductal hyperplasia was the most prevalent at 13.9%, followed by papillary lesions, radial scars, flat epithelial atypia and lobular neoplasia. Imaging factors contributed 26.3% of OBx. In 9.8% of cases, NCB was not performed due to client, technical or cytologic factors. Overall, 261(32.1%) lesions were malignant at OBx. Upgrade rates varied from 0 to 100%, depending on the specific indication for OBx. CONCLUSIONS: Surgical biopsy remains a valuable method of last resort for breast cancer diagnosis but strategies to limit benign breast surgery merit attention as a public health issue.

Test of Special Relativity Using a Fiber Network of Optical Clocks.

Phase compensated optical fiber links enable high accuracy atomic clocks separated by thousands of kilometers to be compared with unprecedented statistical resolution. By searching for a daily variation of the frequency difference between four strontium optical lattice clocks in different locations throughout Europe connected by such links, we improve upon previous tests of time dilation predicted by special relativity. We obtain a constraint on the Robertson-Mansouri-Sexl parameter |α|≲1.1×10^{-8}, quantifying a violation of time dilation, thus improving by a factor of around 2 the best known constraint obtained with Ives-Stilwell type experiments, and by 2 orders of magnitude the best constraint obtained by comparing atomic clocks. This work is the first of a new generation of tests of fundamental physics using optical clocks and fiber links. As clocks improve, and as fiber links are routinely operated, we expect that the tests initiated in this Letter will improve by orders of magnitude in the near future.

The relationship between cognitive impairment, mortality and discharge characteristics in a large cohort of older adults with unscheduled admissions to an acute hospital: a retrospective observational study.

Background: older people with dementia admitted to hospital for acute illness have higher mortality and longer hospital stays compared to those without dementia. Cognitive impairment (CI) is common in older people, and they may also be at increased risk of poor outcomes. Methods: retrospective observational study of unscheduled admissions aged ≥75 years. Admission characteristics, mortality rates and discharge outcomes were compared between three groups: (i) known dementia diagnosis (DD), (ii) CI but no diagnosis of dementia and (iii) no CI. Results: of 19,269 admissions (13,652 patients), 19.8% had a DD, 11.6% had CI and 68.6% had neither. Admissions with CI or DD were older and had more females than those with no CI, and were more likely to be admitted through the Emergency Department (88.4% and 90.7%, versus 82.0%) and to medical wards (89.4% and 84.4%, versus 76.8%). Acuity levels at admission were similar between the groups. Patients with CI or DD had more admissions at 'high risk' from malnutrition than patients with no CI (28.0% and 33.7% versus 17.5%), and a higher risk of dying in hospital (11.8% [10.5-13.3] and 10.8% [9.8-11.9] versus (6.6% [6.2-7.0])). Conclusions: the admission characteristics, mortality and length of stay of patients with CI resemble those of patients with diagnosed dementia. Whilst attention has been focussed on the need for additional support for people with dementia, patients with CI, which may include those with undiagnosed dementia or delirium, appear to have equally bad outcomes from hospitalisation.

Dietitians' practice in giving carbohydrate advice in the management of type 2 diabetes: a mixed methods study.

BACKGROUND: Carbohydrate is accepted as the principal nutrient affecting blood glucose in diabetes; however, current guidelines are unable to specify the optimal quantity of carbohydrate for glycaemic control. No studies exist that describe current practice amongst healthcare professionals giving carbohydrate advice in type 2 diabetes. The present study aims to improve understanding of the degree of variation in the current practice of UK registered dietitians (RDs) by describing how RDs advise patients. METHODS: UK RDs were contacted through national networks and asked to complete an online survey, which was analysed using stata, version 12 (StataCorp, College Station, TX, USA). Three consultations between dietitians and patients with type 2 diabetes were observed, followed by semi-structured interviews with the dietitians. RESULTS: In total, 320 complete survey responses were received. Dietitians' advice varied according to expertise, training and confidence, and the complexity of the patient's blood glucose treatment. Some 48% (n = 154) of respondents advised patients to restrict carbohydrate intake either occasionally or frequently, with 35.6% (n = 114) considering 30-39% of total energy from carbohydrate to be a realistic expectation. The overall theme from the interviews was 'Conflicting Priorities', with three sub-themes: (i) how treatment decisions are made; (ii) the difference between empowerment and advice; and (iii) contradictory advice. A disparity existed between what was observed and interview data on how dietitians rationalise the type of carbohydrate advice provided. CONCLUSIONS: Dietitians' advice varies for a number of reasons. Consensus exists in some areas (e.g. carbohydrate awareness advice); however, clear definitions of such terms are lacking. Clarification of interventions may improve the consistency of approach and improve patient outcomes.

Transitions in mesocarp colour of mango fruits kept under variable temperatures.

The impact of variable temperatures on mesocarp colour development and physico-chemical changes of mango fruits cv. Langra during ripening has been investigated. Physiological mature mango fruits were kept in temperature regulated chambers (20 and 25 °C) and at room temperature (29.8-33.6 °C). Progress in development of mesocarp colour, ß-carotene, sensory quality (SQ) and total soluble solids (TSS) content of fruits were analysed periodically from 48 to 168 h of ripening period. The progress of ripening period was accompanied by an overall increase in colorimetric value redness (a*), yellowness (b*), chroma or saturation (C*), a reduction in lightness (L*) and hue angle (h0) values. Colour development was found to be more in fruits ripened at higher temperatures than the fruits at lower temperature. ß-carotene content of pulp improved with ripening of fruits up to 120 h of ripening period. Fruits ripened at 25 °C recorded maximum sensory quality score. Pearson's correlation matrix studies revealed that fruit mesocarp colour a*, b*, C* values were directly correlated with ß-carotene, SQ and TSS with progress of ripening period.

Physico-chemical changes during progressive ripening of mango (Mangifera indica L.) cv. Dashehari under different temperature regimes.

The effect of different temperature regimes on ripening quality of mango cv. Dashehari was investigated. Fruits were kept at 20, 25 °C in temperature controlled chambers and at room temperature. Fruits were analyzed periodically for physico-chemical characteristics after every 24 h interval up to 168 h of ripening period. Development of soluble solid contents (SSC), flesh softening and physiological loss of weight of fruits occurred progressively during ripening. Progression of ripening changes in fruit were found to be less at 20 and 25 °C than at room temperature. ß-carotene content of pulp improved with ripening but declined after 144 h. Sensory quality (SQ) of mangoes ripened at lower temperature maintained for longer duration and were more acceptable than fruits ripened at room temperature. Pearson's correlation matrix studies showed the inverse relationship of quality parameters SSC, ß-carotene and SQ with firmness and titratable acidity during progressive ripening of fruits. Further, principal component analysis for extensive view of changes in quality parameters and their contribution to overall variability revealed that sensory quality (F1) contributed to maximum variation in ripening indices of fruit.

Observation versus late reintroduction of letrozole as adjuvant endocrine therapy for hormone receptor-positive breast cancer (ANZ0501 LATER): an open-label randomised, controlled trial.

BACKGROUND: Despite the effectiveness of adjuvant endocrine therapy in preventing breast cancer recurrence, breast cancer events continue at a high rate for at least 10 years after completion of therapy. PATIENTS AND METHODS: This randomised open label phase III trial recruited postmenopausal women from 29 Australian and New Zealand sites, with hormone receptor-positive early breast cancer, who had completed ≥4 years of endocrine therapy [aromatase inhibitor (AI), tamoxifen, ovarian suppression, or sequential combination] ≥1 year prior, to oral letrozole 2.5 mg daily for 5 years, or observation. Treatment allocation was by central computerised randomisation, stratified by institution, axillary node status and prior endocrine therapy. The primary outcome was invasive breast cancer events (new invasive primary, local, regional or distant recurrence, or contralateral breast cancer), analysed by intention to treat. The secondary outcomes were disease-free survival (DFS), overall survival, and safety. RESULTS: Between 16 May 2007 and 14 March 2012, 181 patients were randomised to letrozole and 179 to observation (median age 64.3 years). Endocrine therapy was completed at a median of 2.6 years before randomisation, and 47.5% had tumours of >2 cm and/or node positive. At 3.9 years median follow-up (interquartile range 3.1-4.8), 2 patients assigned letrozole (1.1%) and 17 patients assigned observation (9.5%) had experienced an invasive breast cancer event (difference 8.4%, 95% confidence interval 3.8% to 13.0%, log-rank test P = 0.0004). Twenty-four patients (13.4%) in the observation and 14 (7.7%) in the letrozole arm experienced a DFS event (log-rank P = 0.067). Adverse events linked to oestrogen depletion, but not serious adverse events, were more common with letrozole. CONCLUSION: These results should be considered exploratory, but lend weight to emerging data supporting longer duration endocrine therapy for hormone receptor-positive breast cancer, and offer insight into reintroduction of AI therapy. CLINICAL TRIALS NUMBER: Australian New Zealand Clinical Trials Registry (www.anzctr.org.au), ACTRN12607000137493.

Axl receptor tyrosine kinase is a potential therapeutic target in renal cell carcinoma.

BACKGROUND: Axl plays multiple roles in tumourigenesis in several cancers. Here we evaluated the expression and biological function of Axl in renal cell carcinoma (RCC). METHODS: Axl expression was analysed in a tissue microarray of 174 RCC samples by immunostaining and a panel of 11 normal tumour pairs of human RCC tissues by western blot, as well as in RCC cell lines by both western blot and quantitative PCR. The effects of Axl knockdown in RCC cells on cell growth and signalling were investigated. The efficacy of a humanised Axl targeting monoclonal antibody hMAb173 was tested in histoculture and tumour xenograft. RESULTS: We have determined by immunohistochemistry (IHC) that Axl is expressed in 59% of RCC array samples with moderate to high in 20% but not expressed in normal kidney tissue. Western blot analysis of 11 pairs of tumour and adjacent normal tissue show high Axl expression in 73% of the tumours but not normal tissue. Axl is also expressed in RCC cell lines in which Axl knockdown reduces cell viability and PI3K/Akt signalling. The Axl antibody hMAb173 significantly induced RCC cell apoptosis in histoculture and inhibited the growth of RCC tumour in vivo by 78%. The hMAb173-treated tumours also had significantly reduced Axl protein levels, inhibited PI3K signalling, decreased proliferation, and induced apoptosis. CONCLUSIONS: Axl is highly expressed in RCC and critical for RCC cell survival. Targeting Axl is a potential approach for RCC treatment.