Histone methylation regulates reproductive diapause in Drosophila melanogaster.

Fluctuating environments threaten fertility and viability. To better match the immediate, local environment, many organisms adopt alternative phenotypic states, a phenomenon called "phenotypic plasticity." Natural populations that predictably encounter fluctuating environments tend to be more plastic than conspecific populations that encounter a constant environment, suggesting that phenotypic plasticity can be adaptive. Despite pervasive evidence of such "adaptive phenotypic plasticity," gene regulatory mechanisms underlying plasticity remains poorly understood. Here we test the hypothesis that environment-dependent phenotypic plasticity is mediated by epigenetic factors. To test this hypothesis, we exploit the adaptive reproductive arrest of Drosophila melanogaster females, called diapause. Using an inbred line from a natural population with high diapause plasticity, we demonstrate that diapause is determined epigenetically: only a subset of genetically identical individuals enter diapause and this diapause plasticity is epigenetically transmitted for at least three generations. Upon screening a suite of epigenetic marks, we discovered that the active histone marks H3K4me3 and H3K36me1 are depleted in diapausing ovaries. Using ovary-specific knockdown of histone mark writers and erasers, we demonstrate that H3K4me3 and H3K36me1 depletion promotes diapause. Given that diapause is highly polygenic, that is, distinct suites of alleles mediate diapause plasticity across distinct genotypes, we also investigated the potential for genetic variation in diapause-determining epigenetic marks. Specifically, we asked if these histone marks were similarly depleted in diapause of a genotypically distinct line. We found evidence of divergence in both the gene expression program and histone mark abundance. This study reveals chromatin determinants of phenotypic plasticity and suggests that these determinants may be genotype-dependent, offering new insight into how organisms may exploit and evolve epigenetic mechanisms to persist in fluctuating environments.

Clinico-pathologic relationships with Ki67 and its change with short-term aromatase inhibitor treatment in primary ER + breast cancer: further results from the POETIC trial (CRUK/07/015).

PURPOSE: Ki67 assessed at diagnosis (Ki67baseline) is an important prognostic factor in primary oestrogen receptor-positive (ER +) breast cancer. Proportional change in Ki67 after 2 weeks (∆Ki672week) is associated with clinical benefit from endocrine therapies and residual Ki67 (Ki672week) with recurrence-free survival. The aim was to define the association between Ki67baseline and after aromatase inhibitor (AI) exposure ∆Ki672week and Ki672week with key prognostic and biologic factors utilising data from the POETIC study. PATIENTS AND METHODS: In POETIC 4480 postmenopausal patients with primary ER and/or PgR + breast cancer were randomised 2:1 to 2 weeks' presurgical AI (anastrozole or letrozole) or no presurgical treatment (control). Ki67 was measured centrally in core-cut biopsies taken prior to AI and in core-cuts or the excision biopsy at surgery. Relationships between the Ki67 and biologic factors were explored using linear regression. RESULTS: Established associations of Ki67baseline with biologic factors including PgR status, tumour grade, tumour size, histological subtype, nodal status, and vascular invasion were confirmed in the HER2- subpopulation. In the HER2 + subpopulation only grade and tumour size were significantly associated with Ki67baseline. In control group Ki672week was 18% lower than Ki67baseline (p < 0.001) when Ki672week was measured in excision biopsies but not when measured in core-cuts. Median suppression by AIs (∆Ki672week) was 79.3% (IQR: -89.9 to -54.6) and 53.7% (IQR: -78.9 to -21.1) for HER2-negative and HER2-positive cases, respectively. Significantly less suppression occurred in PgR- vs PgR + and HER2 + vs HER2- tumours which remained apparent after adjustment for 2-week sample type. CONCLUSIONS: The magnitude of this study allowed characterisation of relationships between Ki67baseline, ∆Ki672week and Ki672week with high degrees of confidence providing a reference source for other studies. Lower values of Ki67 occur when measured on excision biopsies and could lead to apparent but artefactual decreases in Ki67: this should be considered when either ∆Ki672week or Ki672week is used in routine clinical practice to aid treatment decisions or in clinical trials assessing new drug therapies.

Prevention of lymphoedema after axillary clearance by external compression sleeves PLACE randomised trial results. Effects of high BMI.

Around 25% of women undergoing Axillary Clearance (ANC) develop lymphedema (LE). Intervention with a compression garment is recommended to prevent LE but no randomised evidence exists to support this strategy. METHODS: A randomised trial tested standard management versus application of graduated compression garments (20-24 mmHg) to affected arm, for 1 year. Women with node positive breast cancer (n = 1300) undergoing ANC consented to arm volume measurements and those developing a 4-9% relative arm volume increase (RAVI) (subclinical LE) within 9 months post-surgery were randomised. Primary outcome was proportion of patients developing LE (RAVI > 10%) by 24-months in each group. Secondary endpoints included Quality of life in each group. RESULTS: In total 143 patients were randomised (74 no sleeve: 69 compression sleeve) between October 2010 and November 2015. The lymphoedema rate at 24 months in the 'no sleeve' group was at 41%, similar to the 'sleeve' group (30%: p = 0.32). Thirtytwo patients randomised to the 'no sleeve' group had a sleeve applied within 24 months. Body Mass Index (BMI) at randomisation predicted LE at any time point HR 1.04 (CI 1.01-1.08; p = 0.01). Patients with obesity (BMI > 30) had higher rates of LE in both groups (46%) compared to those with BMI < 30 (24%). No difference between patients was found in either group in changes in QoL. Compression sleeves applied after development of LE improved QoL scores (FACT-B p = 0.007:TOI p = 0.042). CONCLUSION: Early intervention with External Compression garments does not prevent clinical LE, particularly in women with a high BMI > 30. The use of prophylactic garments in subclinical LE (RAVI < 9%) is unwarranted.

Relationship between ER expression by IHC or mRNA with Ki67 response to aromatase inhibition: a POETIC study.

BACKGROUND: In clinical practice, oestrogen receptor (ER) analysis is almost entirely by immunohistochemistry (IHC). ASCO/CAP recommends cut-offs of < 1% (negative) and 1-10% (low) cells positive. There is uncertainty whether patients with ER low tumours benefit from endocrine therapy. We aimed to assess IHC and mRNA cut-points for ER versus biological response of primary breast cancer to 2 weeks' aromatase inhibitor treatment as measured by change in Ki67. METHODS: Cases were selected from the aromatase inhibitor treatment group of POETIC. We selected the 15% with the poorest Ki67 response (PR, < 40% Ki67 suppression, n = 230) and a random 30% of the remainder categorised as intermediate (IR, 40-79% Ki67 suppression, n = 150) and good-responders (GR, ≥ 80% Ki67 suppression, n = 230) from HER2 - group. All HER2 + cases available were selected irrespective of their response category (n = 317). ER expression was measured by IHC and qPCR. RESULTS: ER IHC was available from 515 HER2 - and 186 HER2 + tumours and ER qPCR from 367 HER2 - and 171 HER2 + tumours. Ninety-one percentage of patients with ER IHC < 10% were PRs with similar rates in HER2 - and HER2 + cases. At or above ER IHC 10% substantial numbers of patients showed IR or GR. Similar proportions of patients were defined by cut-points of ER IHC < 10% and ER mRNA < 5 units. In addition, loss of PgR expression altered ER anti-proliferation response with 92% of PgR - cases with ER IHC < 40% being PRs. CONCLUSIONS: There was little responsiveness at IHC < 10% and no distinction between < 1% and 1-10% cells positive. Similar separation of PRs from IR/GRs was achieved by IHC and mRNA.

Combined Perioperative Lapatinib and Trastuzumab in Early HER2-Positive Breast Cancer Identifies Early Responders: Randomized UK EPHOS-B Trial Long-Term Results.

PURPOSE: EPHOS-B aimed to determine whether perioperative anti-HER2 therapy inhibited proliferation and/or increased apoptosis in HER2-positive breast cancer. PATIENTS AND METHODS: This randomized phase II, two-part, multicenter trial included newly diagnosed women with HER2-positive invasive breast cancer due to undergo surgery. Patients were randomized to: part 1 (1:2:2), no treatment (control), trastuzumab or lapatinib; part 2 (1:1:2) control, trastuzumab, or lapatinib and trastuzumab combination. Treatment was given for 11 days presurgery. Coprimary endpoints were change in Ki67 and apoptosis between baseline and surgery tumor samples (biologic response: ≥30% change). Central pathology review scored residual cancer burden (RCB). Relapse-free survival (RFS) explored long-term effects. RESULTS: Between November 2010 and September 2015, 257 patients were randomized (part 1: control 22, trastuzumab 57, lapatinib 51; part 2: control 29, trastuzumab 32, combination 66). Ki67 response was evaluable for 223 patients: in part 1 Ki67 response occurred in 29/44 (66%) lapatinib versus 18/49 (37%) trastuzumab (P = 0.007) and 1/22 (5%) control (P < 0.0001); in part 2 in 36/49 (74%) combination versus 14/31 (45%) trastuzumab (P = 0.02) and 2/28 (7%) control (P < 0.0001). No significant increase in apoptosis after 11 days was seen in treatment groups. Six patients achieved complete pathologic response (pCR, RCB0) and 13 RCB1, all but two in the combination group. After 6 years median follow-up, 28 (11%) had recurrence and 19 (7%) died. No recurrences or deaths were observed among patients who achieved a pCR. Ki67% falls ≥50% associated with fewer recurrences (P = 0.002). CONCLUSIONS: Early response after short duration anti-HER2 dual therapy identifies cancers dependent on the HER2 pathway providing a strategy for exploring risk-adapted individualized treatment de-escalation.

Improving DVLA advice provided to the patients with acute coronary syndrome upon discharge.

Acute coronary syndrome (ACS) and coronary intervention can significantly impair patients' ability to drive and, therefore, the Driver & Vehicle Licensing Agency (DVLA) provides relevant guidance for patients and healthcare professionals on driving in order to safeguard patients, passengers and public in general. The initial pre-teaching cohort analysis revealed that 12.9% of the discharge summaries had documented driving advice and only 3.23% were in accordance with the DVLA guidance. Our primary aim was to increase the provision of appropriate driving advice to >90%. Secondary aims were to improve the quality of the written advice and to increase junior doctors' awareness and confidence in doing so. We created a template with standardised driving advice with specific guidance for group 1 and group 2 drivers, delivered formal and informal teaching, and distributed information leaflets. These measures led to an overall improvement in provision of correct advice to >90%. We demonstrated how simple measures of introducing a standardised driving advice template and conducting formal and informal teaching could significantly improve the quality of current practice pertaining to the DVLA's driving restrictions in ACS patients. The successful strategies employed by us can be utilised by other trusts across the UK to promote person-centred care and improve patient safety.

Trends in the Regulation of Per- and Polyfluoroalkyl Substances (PFAS): A Scoping Review.

Products containing per- and polyfluoroalkyl substances (PFAS) have been used for decades in industrial and consumer products. These compounds are persistent in the environment, bioaccumulative, and some are toxic to humans and other animals. Since the early 2000s, laws, policies, and regulations have been implemented to reduce the prevalence of PFAS in the environment and exposures to PFAS. We conducted a scoping literature review to identify how PFAS are regulated internationally, at the U.S. national level, and at the U.S. state level, as well as drivers of and challenges to implementing PFAS regulations in the U.S. This review captured peer-reviewed scientific literature (e.g., PubMed), grey literature databases (e.g., SciTech Premium Collection), Google searches, and targeted websites (e.g., state health department websites). We identified 454 relevant documents, of which 61 discussed the non-U.S. PFAS policy, 214 discussed the U.S. national-level PFAS policy, and 181 discussed the U.S. state-level PFAS policy. The drivers of and challenges to PFAS regulation were identified through qualitative analysis. The drivers of PFAS policy identified were political support for regulation, social awareness of PFAS, economic resource availability, and compelling scientific evidence. The challenges to implementing PFAS regulations were political limitations, economic challenges, unclear scientific evidence, and practical challenges. The implications for PFAS policy makers and other stakeholders are discussed.

Impact of the menstrual cycle on commercial prognostic gene signatures in oestrogen receptor-positive primary breast cancer.

PURPOSE: Changes occur in the expression of oestrogen-regulated and proliferation-associated genes in oestrogen receptor (ER)-positive breast tumours during the menstrual cycle. We investigated if Oncotype® DX recurrence score (RS), Prosigna® (ROR) and EndoPredict® (EP/EPclin) prognostic tests, which include some of these genes, vary according to the time in the menstrual cycle when they are measured. METHODS: Pairs of test scores were derived from 30 ER-positive/human epidermal growth factor receptor-2-negative tumours sampled at two different points of the menstrual cycle. Menstrual cycle windows were prospectively defined as either W1 (days 1-6 and 27-35; low oestrogen and low progesterone) or W2 (days 7-26; high oestrogen and high or low progesterone). RESULTS: The invasion module score of RS was lower (- 10.9%; p = 0.098), whereas the ER (+ 16.6%; p = 0.046) and proliferation (+ 7.3%; p = 0.13) module scores were higher in W2. PGR expression was significantly increased in W2 (+ 81.4%; p = 0.0029). Despite this, mean scores were not significantly different between W1 and W2 for any of the tests and the two measurements showed high correlation (r = 0.72-0.93). However, variability between the two measurements led to tumours being assigned to different risk categories in the following proportion of cases: RS 22.7%, ROR 27.3%, EP 13.6% and EPclin 13.6%. CONCLUSION: There are significant changes during the menstrual cycle in the expression of some of the genes and gene module scores comprising the RS, ROR and EP/EPclin scores. These did not affect any of the prognostic scores in a systematic fashion, but there was substantial variability in paired measurements.

Effect of Celecoxib vs Placebo as Adjuvant Therapy on Disease-Free Survival Among Patients With Breast Cancer: The REACT Randomized Clinical Trial.

IMPORTANCE: Patients with breast cancer remain at risk of relapse after adjuvant therapy. Celecoxib has shown antitumor effects in preclinical models of human breast cancer, but clinical evidence is lacking. OBJECTIVE: To evaluate the role of celecoxib as an addition to conventional therapy for women with ERBB2 (formerly HER2)-negative primary breast cancer. DESIGN, SETTING, AND PARTICIPANTS: The Randomized European Celecoxib Trial (REACT) was a phase 3, randomized, double-blind study conducted in 160 centers across the UK and Germany testing 2 years of adjuvant celecoxib vs placebo among 2639 patients recruited between January 19, 2007, and November 1, 2012, with follow-up 10 years after treatment completion. Eligible patients had completely resected breast cancer with local and systemic therapy according to local practice. Patients with ERBB2-positive or node-negative and T1, grade 1 tumors were not eligible. Randomization was in a 2:1 ratio between celecoxib or placebo. Statistical analysis was performed from May 5, 2019, to March 5, 2020. INTERVENTIONS: Patients received celecoxib, 400 mg, or placebo once daily for 2 years. MAIN OUTCOMES AND MEASURES: The primary end point was disease-free survival (DFS), analyzed in the intention-to-treat population using Cox proportional hazards regression and log-rank analysis. Follow-up is complete. RESULTS: A total of 2639 patients (median age, 55.2 years [range, 26.8-86.0 years]) were recruited; 1763 received celecoxib, and 876 received placebo. Most patients' tumors (1930 [73%]) were estrogen receptor positive or progesterone receptor positive and ERBB2 negative. A total of 1265 patients (48%) had node-positive disease, and 1111 (42%) had grade 3 tumors. At a median follow-up of 74.3 months (interquartile range, 61.4-93.6 years), DFS events had been reported for 487 patients (19%): 18% for those who received celecoxib (n = 323; 5-year DFS rate = 84%) vs 19% for those who received placebo (n = 164; 5-year DFS rate = 83%); the unadjusted hazard ratio was 0.97 (95% CI, 0.80-1.17; log-rank P = .75). Rates of toxic effects were low across both treatment groups, with no evidence of a difference. CONCLUSIONS AND RELEVANCE: In this randomized clinical trial, patients showed no evidence of a DFS benefit for 2 years' treatment with celecoxib compared with placebo as adjuvant treatment of ERBB2-negative breast cancer. Longer-term treatment or use of a higher dose of celecoxib may lead to a DFS benefit, but further studies would be required to test this possibility. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02429427 and isrctn.org Identifier: ISRCTN48254013.

What Motivates Smokers to Switch to ENDS? A Qualitative Study of Perceptions and Use.

Switching completely from cigarettes to electronic nicotine delivery systems (ENDS) may reduce health risks for addicted smokers. This paper provides information about perceptions and other factors that may influence smokers' ENDS use and substitution for cigarettes. We conducted 12 online focus groups (N = 61) among smokers who had never tried using ENDS (Never Users, N = 11), currently used both cigarettes and ENDS (Dual Users, N = 21), used but discontinued ENDS (Rejectors, N = 14), and switched completely to ENDS use (Switchers, N = 15). Thematic analysis was used to interpret the transcripts. Participants described initial interest in trying ENDS in hopes of quitting smoking and because of convenience (i.e., due to rules, regulations, or social norms). Risk perceptions and higher prices relative to cigarettes were reported as disadvantages of ENDS that discouraged initiation. Dual Users and Rejectors reported product problems (e.g., products breaking) and dissatisfaction (i.e., inability to satisfy cravings for cigarettes) as factors that lowered their substitutability for cigarettes or led to discontinuing ENDS use. Switchers indicated that satisfaction, lack of product problems, and perceived safety facilitated successfully switching from cigarette smoking to exclusive ENDS use. However, Switchers reported trying many products before they found ones that satisfied their needs. We recommend that policymakers consider the potential impact of tobacco control policies on smokers' motivation and ability to switch completely from cigarettes to ENDS.

Long-term outcome and prognostic value of Ki67 after perioperative endocrine therapy in postmenopausal women with hormone-sensitive early breast cancer (POETIC): an open-label, multicentre, parallel-group, randomised, phase 3 trial.

BACKGROUND: Preoperative and perioperative aromatase inhibitor (POAI) therapy has the potential to improve outcomes in women with operable oestrogen receptor-positive primary breast cancer. It has also been suggested that tumour Ki67 values after 2 weeks (Ki672W) of POAI predicts individual patient outcome better than baseline Ki67 (Ki67B). The POETIC trial aimed to test these two hypotheses. METHODS: POETIC was an open-label, multicentre, parallel-group, randomised, phase 3 trial (done in 130 UK hospitals) in which postmenopausal women aged at least 50 years with WHO performance status 0-1 and hormone receptor-positive, operable breast cancer were randomly assigned (2:1) to POAI (letrozole 2·5 mg per day orally or anastrozole 1 mg per day orally) for 14 days before and following surgery or no POAI (control). Adjuvant treatment was given as per UK standard local practice. Randomisation was done centrally by computer-generated permuted block method (variable block size of six or nine) and was stratified by hospital. Treatment allocation was not masked. The primary endpoint was time to recurrence. A key second objective explored association between Ki67 (dichotomised at 10%) and disease outcomes. The primary analysis for clinical endpoints was by modified intention to treat (excluding patients who withdrew consent). For Ki67 biomarker association and endpoint analysis, the evaluable population included all randomly assigned patients who had paired Ki67 values available. This study is registered with ClinicalTrials.gov, NCT02338310; the European Clinical Trials database, EudraCT2007-003877-21; and the ISRCTN registry, ISRCTN63882543. Recruitment is complete and long-term follow-up is ongoing. FINDINGS: Between Oct 13, 2008, and April 16, 2014, 4480 women were recruited and randomly assigned to POAI (n=2976) or control (n=1504). On Feb 6, 2018, median follow-up was 62·9 months (IQR 58·1-74·1). 434 (10%) of 4480 women had a breast cancer recurrence (280 [9%] POAI; 154 [10%] control), hazard ratio 0·92 (95% CI 0·75-1·12); p=0·40 with the proportion free from breast cancer recurrence at 5 years of 91·0% (95% CI 89·9-92·0) for patients in the POAI group and 90·4% (88·7-91·9) in the control group. Within the POAI-treated HER2-negative subpopulation, 5-year recurrence risk in women with low Ki67B and Ki672W (low-low) was 4·3% (95% CI 2·9-6·3), 8·4% (6·8-10·5) with high Ki67B and low Ki672W (high-low) and 21·5% (17·1-27·0) with high Ki67B and Ki672W (high-high). Within the POAI-treated HER2-positive subpopulation, 5-year recurrence risk in the low-low group was 10·1% (95% CI 3·2-31·3), 7·7% (3·4-17·5) in the high-low group, and 15·7% (10·1-24·4) in the high-high group. The most commonly reported grade 3 adverse events were hot flushes (20 [1%] of 2801 patients in the POAI group vs six [<1%] of 1400 in the control group) and musculoskeletal pain (29 [1%] vs 13 [1%]). No treatment-related deaths were reported. INTERPRETATION: POAI has not been shown to improve treatment outcome, but can be used without detriment to help select appropriate adjuvant therapy based on tumour Ki67. Most patients with low Ki67B or low POAI-induced Ki672W do well with adjuvant standard endocrine therapy (giving consideration to clinical-pathological factors), whereas those whose POAI-induced Ki672W remains high might benefit from further adjuvant treatment or trials of new therapies. FUNDING: Cancer Research UK.

A method to measure the partitioning coefficient of volatile organic compounds in nanoparticles.

The partitioning behavior of volatile organic compounds (VOCs) into nanoparticles is less studied compared to those of semivolatile organic compounds (SVOCs) because of the lower concentration of the VOCs that is expected to partition into particles. One challenge in measuring the accurate partition coefficient of VOCs is quantifying their low mass fraction that sorbed on nanoparticles and differentiating them from the high VOC concentrations present in the gas-phase. Systematically characterizing the partitioning coefficient at a specific environmental condition is also difficult when sampling in the field. During field sampling, thermal and non-thermal issues such as sampling artifacts and non-equilibrium conditions because of a dynamic environment often result in considerable variability in the measured partition coefficients. In this study, we developed a bench-scale system that can achieve precise control of the experimental condition (e.g., relative humidity, temperature, and particle composition) and allow us to measure the low concentration of 1,2-dichlorobenzene in the particles. A similar set up can be used to study the low mass fraction of other VOCs partitioning in nanoparticles. The detailed but uncomplicated system setup may assist other researchers that investigate the global fate and transport and health effects of VOCs.•A bench-scale system was built in the laboratory to study the gas-to-particle partitioning•Experimental conditions can be controlled and easily varied•The system enables the systematic study of a single environmental factor on the partitioning process.

Numeracy and memory for risk probabilities and risk outcomes depicted on cigarette warning labels.

OBJECTIVE: Greater numeracy is associated with higher likelihood to quit smoking. We examined whether numeracy supports learning of numeric health-risk information and, in turn, greater risk perceptions and quit intentions. METHOD: Adult smokers (N = 696) viewed text warnings with numeric risk information four times each in one of three warning-label types (text-only, low-emotion pictorial [i.e., with image], high-emotion pictorial). They completed posttest measures immediately or 6 weeks later. Emotional reactions to warnings were reported the second time participants viewed the warnings. Numeracy, memory for risk probabilities and risk outcomes, risk perceptions, and quit intentions were assessed postexposures. RESULTS: Memory for risk probabilities and risk outcomes depended on warning-label type and posttest timing. Consistent with memory-consolidation theory, memory for high- versus low-emotion labels was lower immediately, but declined less for high-than low-emotion labels. Label memory was similar between conditions at 6 weeks. Numeracy predicted overall superior memory (especially for risk probabilities) controlling for health literacy and education. It also indirectly predicted greater risk perceptions and quit intentions via memory. In exploratory analyses, however, the superior recall of risk probabilities of smoking among those higher in numeracy was associated with lower risk perceptions. CONCLUSIONS: Numeracy is associated with superior risk memory, which relates to greater risk perceptions and quit intentions. More numerate and educated smokers may be better able to quit due to their superior learning of smoking's risks. (PsycInfo Database Record (c) 2020 APA, all rights reserved).

Increases in arm volume predict lymphoedema and quality of life deficits after axillary surgery: a prospective cohort study.

BACKGROUND: Lymphoedema develops after axillary clearance (ANC) in 25% of patients. This prospective, multi-centre study compared multi-frequency bioimpedance spectroscopy (BIS) with arm volume measurement to: (1) determine which test has better diagnostic accuracy, (2) identify factors predicting development of lymphoedema, and its effect on quality-of-life. METHODS: Participants (N = 1100) underwent measurements pre and post-ANC surgery for breast cancer. Relative arm volume increase (RAVI) of >10% diagnosed lymphoedema. Predictors of lymphoedema were determined using logistic regression. Optimal diagnostic method was assessed using diagnostic accuracy. Quality-of-life was assessed using the FACT B + 4 questionnaire. RESULTS: Lymphoedema was diagnosed in 22.8% women using RAVI > 10%, 45.6% using BIS criteria, while 24.5% underwent compression sleeve application by 24 months. BMI > 30 was an independent factor for both development (p = 0.005) and progression (p = 0.015) of lymphoedema. RAVI at 1 month, BMI > 30 and number of involved nodes contributed to a novel scoring model to predict lymphoedema by 36 months. Larger decreases in QoL scores post-surgery occurred in lymphoedema patients (p < 0.001). Progression to moderate lymphoedema occurred in 15% patients after sleeve application. CONCLUSIONS: RAVI measurement was the best diagnostic tool for lymphoedema. BIS alone is not appropriate for lymphoedema screening or diagnosis. BMI > 30 predicted lymphoedema diagnosis and progression.

Homologous recombination DNA repair deficiency and PARP inhibition activity in primary triple negative breast cancer.

Triple negative breast cancer (TNBC) encompasses molecularly different subgroups, with a subgroup harboring evidence of defective homologous recombination (HR) DNA repair. Here, within a phase 2 window clinical trial, RIO trial (EudraCT 2014-003319-12), we investigate the activity of PARP inhibitors in 43 patients with untreated TNBC. The primary end point, decreased Ki67, occured in 12% of TNBC. In secondary end point analyses, HR deficiency was identified in 69% of TNBC with the mutational-signature-based HRDetect assay. Cancers with HRDetect mutational signatures of HR deficiency had a functional defect in HR, assessed by impaired RAD51 foci formation on end of treatment biopsy. Following rucaparib treatment there was no association of Ki67 change with HR deficiency. In contrast, early circulating tumor DNA dynamics identified activity of rucaparib, with end of treatment ctDNA levels suppressed by rucaparib in mutation-signature HR-deficient cancers. In ad hoc analysis, rucaparib induced expression of interferon response genes in HR-deficient cancers. The majority of TNBCs have a defect in DNA repair, identifiable by mutational signature analysis, that may be targetable with PARP inhibitors.

A Randomized, Open-label, Presurgical, Window-of-Opportunity Study Comparing the Pharmacodynamic Effects of the Novel Oral SERD AZD9496 with Fulvestrant in Patients with Newly Diagnosed ER+ HER2- Primary Breast Cancer.

PURPOSE: Fulvestrant, the first-in-class selective estrogen receptor (ER) degrader (SERD), is clinically effective in patients with ER+ breast cancer, but it has administration and pharmacokinetic limitations. Pharmacodynamic data suggest complete ER degradation is not achieved at fulvestrant's clinically feasible dose. This presurgical study (NCT03236974) compared the pharmacodynamic effects of fulvestrant with AZD9496, a novel, orally bioavailable, nonsteroidal, potent SERD, in treatment-naïve patients with ER+ HER2- primary breast cancer awaiting curative intent surgery. PATIENTS AND METHODS: Patients were randomized 1:1 to receive AZD9496 250 mg twice daily from day 1 for 5-14 days, or fulvestrant 500 mg on day 1. On-treatment imaging-guided core tumor biopsies were taken between day 5 and 14 and compared with pretreatment diagnostic biopsies. The primary objective was to compare the effects of AZD9496 and fulvestrant on ER expression. Secondary objectives included changes in progesterone receptor (PR) and Ki-67 pharmacokinetic/pharmacodynamic relationships and safety. RESULTS: Forty-six women received treatment (AZD9496 n = 22; fulvestrant n = 24); 35 paired biopsies were evaluable (AZD9496 n = 15; fulvestrant n = 20). The least square mean estimate for ER H-score reduction was 24% after AZD9496 versus 36% after fulvestrant treatment (P = 0.86). AZD9496 also reduced PR H-scores (-33.3%) and Ki-67 levels (-39.9%) from baseline, but was also not superior to fulvestrant (PR: -68.7%, P = 0.97; Ki-67: -75.4%, P = 0.98). No new safety findings were identified. CONCLUSIONS: This was the first presurgical study to demonstrate that an oral SERD affects its key biological targets. However, AZD9496 was not superior to fulvestrant at the dose tested.

International randomised controlled trial for the treatment of newly diagnosed EWING sarcoma family of tumours - EURO EWING 2012 Protocol.

BACKGROUND: Although there have been multiple randomised trials in newly diagnosed Ewing sarcoma family of tumours (ESFT) and these have been conducted over many years and involved many international cooperative groups, the outcomes for all stages of disease have plateaued. Internationally, the standard treatment of ESFT is not defined, and there is a need to add new agents other than conventional chemotherapy to improve outcomes. This trial will compare two different induction/consolidation chemotherapy regimens: (1) vincristine, ifosfamide, doxorubicin and etoposide (VIDE) induction and vincristine, actinomycin D, ifosfamide or cyclophosphamide, or busulfan and mephalan (VAI/VAC/BuMel) consolidation and (2) vincristine, doxorubicin, cyclophosphamide, ifosfamide and etoposide (VDC/IE) induction and ifosfamide and etoposide, vincristine and cyclophosphamide, vincristine, actinomycin D and ifosfamide, or busulfan and mephalan (IE/VC/VAI/BuMel) consolidation (randomisation 1, or R1). A second randomisation (R2) will determine whether the addition of zoledronic acid to consolidation chemotherapy, as assigned at R1, is associated with improved clinical outcome. METHODS: EURO EWING 2012 is an international, multicentre, phase III, open-label randomised controlled trial. There are two randomisations: R1 and R2. Patients are randomly assigned at two different time points: at entry to the trial (R1) and following local control therapy (R2). The primary outcome measure is event-free survival. The secondary outcome measures include overall survival, adverse events and toxicity, histological response of the primary tumour, response of the primary tumour, regional lymph nodes or metastases (or both), and achievement of local control at the end of treatment. DISCUSSION: This study will establish which is the "standard regimen" of chemotherapy, taking into account both clinical outcomes and toxicity. This will form the chemotherapy backbone for future interventional studies where we may want to add new targeted agents. It will also determine the role of zoledronic acid in conjunction with the separate EE2008 trial. Any trial in ESFT needs to take into account the rarity of the tumour and consider that international cooperation is needed to provide answers in a timely manner. TRIAL REGISTRATION: Registered with EudraCT number 2012-002107-17 on 26 February 2012. Registered with ISRCTN number 54540667 on 4 November 2013.