Adjuvant bisphosphonate treatment in early breast cancer: meta-analyses of individual patient data from randomised trials

BACKGROUND: Bisphosphonates have profound effects on bone physiology, and could modify the process of metastasis. We undertook collaborative meta-analyses to clarify the risks and benefits of adjuvant bisphosphonate treatment in breast cancer.

METHODS: We sought individual patient data from all unconfounded trials in early breast cancer that randomised between bisphosphonate and control. Primary outcomes were recurrence, distant recurrence, and breast cancer mortality. Primary subgroup investigations were site of first distant recurrence (bone or other), menopausal status (postmenopausal [combining natural and artificial] or not), and bisphosphonate class (aminobisphosphonate [eg, zoledronic acid, ibandronate, pamidronate] or other [ie, clodronate]). Intention-to-treat log-rank methods yielded bisphosphonate versus control first-event rate ratios (RRs).

FINDINGS: We received data on 18 766 women (18 206 [97%] in trials of 2-5 years of bisphosphonate) with median follow-up 5·6 woman-years, 3453 first recurrences, and 2106 subsequent deaths. Overall, the reductions in recurrence (RR 0·94, 95% CI 0·87-1·01; 2p=0·08), distant recurrence (0·92, 0·85-0·99; 2p=0·03), and breast cancer mortality (0·91, 0·83-0·99; 2p=0·04) were of only borderline significance, but the reduction in bone recurrence was more definite (0·83, 0·73-0·94; 2p=0·004). Among premenopausal women, treatment had no apparent effect on any outcome, but among 11 767 postmenopausal women it produced highly significant reductions in recurrence (RR 0·86, 95% CI 0·78-0·94; 2p=0·002), distant recurrence (0·82, 0·74-0·92; 2p=0·0003), bone recurrence (0·72, 0·60-0·86; 2p=0·0002), and breast cancer mortality (0·82, 0·73-0·93; 2p=0·002). Even for bone recurrence, however, the heterogeneity of benefit was barely significant by menopausal status (2p=0·06 for trend with menopausal status) or age (2p=0·03), and it was non-significant by bisphosphonate class, treatment schedule, oestrogen receptor status, nodes, tumour grade, or concomitant chemotherapy. No differences were seen in non-breast cancer mortality. Bone fractures were reduced (RR 0·85, 95% CI 0·75-0·97; 2p=0·02).

INTERPRETATION: Adjuvant bisphosphonates reduce the rate of breast cancer recurrence in the bone and improve breast cancer survival, but there is definite benefit only in women who were postmenopausal when treatment began.

FUNDING: Cancer Research UK, Medical Research Council.

The dual EGFR/HER2 inhibitor lapatinib synergistically enhances the antitumor activity of the histone deacetylase inhibitor panobinostat in colorectal cancer models

As key molecules that drive progression and chemoresistance in gastrointestinal cancers, epidermal growth factor receptor (EGFR) and HER2 have become efficacious drug targets in this setting. Lapatinib is an EGFR/HER2 kinase inhibitor suppressing signaling through the RAS/RAF/MEK (MAP/ERK kinase)/MAPK (mitogen-activated protein kinase) and PI3K (phosphoinositide 3-kinase)/AKT pathways. Histone deacetylase inhibitors (HDACi) are a novel class of agents that induce cell cycle arrest and apoptosis following the acetylation of histone and nonhistone proteins modulating gene expression and disrupting HSP90 function inducing the degradation of EGFR-pathway client proteins. This study sought to evaluate the therapeutic potential of combining lapatinib with the HDACi panobinostat in colorectal cancer (CRC) cell lines with varying EGFR/HER2 expression and KRAS/BRAF/PIK3CA mutations. Lapatinib and panobinostat exerted concentration-dependent antiproliferative effects in vitro (panobinostat range 7.2-30 nmol/L; lapatinib range 7.6-25.8 μmol/L). Combined lapatinib and panobinostat treatment interacted synergistically to inhibit the proliferation and colony formation in all CRC cell lines tested. Combination treatment resulted in rapid induction of apoptosis that coincided with increased DNA double-strand breaks, caspase-8 activation, and PARP cleavage. This was paralleled by decreased signaling through both the PI3K and MAPK pathways and increased downregulation of transcriptional targets including NF-κB1, IRAK1, and CCND1. Panobinostat treatment induced downregulation of EGFR, HER2, and HER3 mRNA and protein through transcriptional and posttranslational mechanisms. In the LoVo KRAS mutant CRC xenograft model, the combination showed greater antitumor activity than either agent alone, with no apparent increase in toxicity. Our results offer preclinical rationale warranting further clinical investigation combining HDACi with EGFR and HER2-targeted therapies for CRC treatment.

Perceived difficulty of various steps of manual small incision cataract surgery among trainees in rural China

Background: The perceived difficulty of steps of manual small incision cataract surgery among trainees in rural China was assessed. Design: Cohort study. Participants: Fifty-two trainees at the end of a manual small incision cataract surgery training programme. Methods: Participants rated the difficulty of 14 surgical steps using a 5-point scale, 1 (very easy) to 5 (very difficult). Demographic and professional information was recorded for trainees. Main Outcome Measure: Mean ratings for surgical steps. Results: Questionnaires were completed by 49 trainees (94.2%, median age 38 years, 8 [16.3%] women). Twenty six (53.1%) had performed ≤50 independent cataract surgeries prior to training. Trainees rated cortical aspiration (mean score±standard deviation=3.10±1.14) the most difficult step, followed by wound construction (2.76±1.08), nuclear prolapse into the anterior chamber (2.74±1.23) and lens delivery (2.51±1.08). Draping the surgical field (1.06±0.242), anaesthetic block administration (1.14±0.354) and thermal coagulation (1.18±0.441) were rated easiest. In regression models, the score for cortical aspiration was significantly inversely associated with performing >50 independent manual small incision cataract surgery surgeries during training (P=0.01), but not with age, gender, years of experience in an eye department or total number of cataract surgeries performed prior to training. Conclusions: Cortical aspiration, wound construction and nuclear prolapse pose the greatest challenge for trainees learning manual small incision cataract surgery, and should receive emphasis during training. Number of cases performed is the strongest predictor of perceived difficulty of key steps. © 2013 Royal Australian and New Zealand College of Ophthalmologists.

Prevalence of corneal astigmatism before cataract surgery in Chinese patients

Purpose: To assess the demographics and distribution of corneal astigmatism before cataract surgery in Chinese patients. Setting: State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou, China. Design: Clinic-based cross-sectional study. Methods: From July 2009 to May 2011, preoperative bilateral partial coherence interferometry (IOLMaster) was performed in consecutive patients having cataract surgery. Patient demographics and keratometric data were recorded. Results: The mean age of the 2849 patients (4831 eyes) was 70.56 years ± 9.55 (SD); there was a predominance of women patients (64.0%). The mean axial length was 23.58 ± 1.13 mm. The mean corneal astigmatism in this cohort was 1.01 D (range 0.05 to 6.59 D). Corneal astigmatism was between 0.25 D and 1.25 D in 67.7% of eyes, 1.25 D or higher in 27.5% eyes, and less than 0.25 D in 4.8% of eyes. Astigmatism was with the rule in 25.1% of eyes, against the rule (ATR) in 58.2% of eyes, and oblique in 16.7% of eyes. The mean steep keratometry measurement was 44.76 ± 1.56 D. Against-the-rule astigmatism increased significantly with older age. Conclusions: Corneal astigmatism largely fell between 0.25 D and 1.25 D in these predominantly elderly female Chinese patients, and ATR astigmatism increased with age. Financial Disclosure: No author has a financial or proprietary interest in any material or method mentioned. © 2012 ASCRS and ESCRS.

The relationship between time attitudes profiles and self-efficacy, sensation seeking, and alcohol use: An exploratory study

A growing body of research has begun to report on time attitudes which specifically refers to an individual's emotional and evaluative feelings toward the past, the present, and the future. The present study used data from the first wave of a longitudinal cohort study in the United Kingdom. Sample 1 consisted of 1580 adolescents (40% female, 1.7% unreported) in Northern Ireland, while Sample 2 consisted of 813 adolescents (46.7% female, 1.4% unreported) in Scotland. Five similar time attitudes profiles emerged in both countries, with one additional "balanced" profile in Scotland. Results show that there were no substantive differences between profiles in terms of socio-demographic indicators. However, in respect of academic, social and emotional self-efficacy, best results were observed for those with Positive, Ambivalent, and Balanced profiles, with the reverse true for those with Negative, Past Negative, and Pessimistic profiles. Positives were also less likely to report using alcohol.