Mechanisms of sensitivity and resistance to CDK4/CDK6 inhibitors in hormone receptor-positive breast cancer treatment.

Cell cycle dysregulation is a hallmark of cancer that promotes eccessive cell division. Cyclin-dependent kinase 4 (CDK4) and cyclin-dependent kinase 6 (CDK6) are key molecules in the G1-to-S phase cell cycle transition and are crucial for the onset, survival, and progression of breast cancer (BC). Small-molecule CDK4/CDK6 inhibitors (CDK4/6i) block phosphorylation of tumor suppressor Rb and thus restrain susceptible BC cells in G1 phase. Three CDK4/6i are approved for the first-line treatment of patients with advanced/metastatic hormone receptor-positive (HR+)/human epidermal growth factor receptor 2-negative (HER2-) BC in combination with endocrine therapy (ET). Though this has improved the clinical outcomes for survival of BC patients, there is no established standard next-line treatment to tackle drug resistance. Recent studies suggest that CDK4/6i can modulate other distinct effects in both BC and breast stromal compartments, which may provide new insights into aspects of their clinical activity. This review describes the biochemistry of the CDK4/6-Rb-E2F pathway in HR+ BC, then discusses how CDK4/6i can trigger other effects in BC/breast stromal compartments, and finally outlines the mechanisms of CDK4/6i resistance that have emerged in recent preclinical studies and clinical cohorts, emphasizing the impact of these findings on novel therapeutic opportunities in BC.

PI3K/AKT/mTOR signaling transduction pathway and targeted therapies in cancer.

The PI3K/AKT/mTOR (PAM) signaling pathway is a highly conserved signal transduction network in eukaryotic cells that promotes cell survival, cell growth, and cell cycle progression. Growth factor signalling to transcription factors in the PAM axis is highly regulated by multiple cross-interactions with several other signaling pathways, and dysregulation of signal transduction can predispose to cancer development. The PAM axis is the most frequently activated signaling pathway in human cancer and is often implicated in resistance to anticancer therapies. Dysfunction of components of this pathway such as hyperactivity of PI3K, loss of function of PTEN, and gain-of-function of AKT, are notorious drivers of treatment resistance and disease progression in cancer. In this review we highlight the major dysregulations in the PAM signaling pathway in cancer, and discuss the results of PI3K, AKT and mTOR inhibitors as monotherapy and in co-administation with other antineoplastic agents in clinical trials as a strategy for overcoming treatment resistance. Finally, the major mechanisms of resistance to PAM signaling targeted therapies, including PAM signaling in immunology and immunotherapies are also discussed.

Fulvestrant plus capivasertib versus placebo after relapse or progression on an aromatase inhibitor in metastatic, oestrogen receptor-positive, HER2-negative breast cancer (FAKTION): overall survival, updated progression-free survival, and expanded biomarker analysis from a randomised, phase 2 trial.

BACKGROUND: Capivasertib, an AKT inhibitor, added to fulvestrant, was previously reported to improve progression-free survival in women with aromatase inhibitor-resistant oestrogen receptor (ER)-positive, HER2-negative advanced breast cancer. The benefit appeared to be independent of the phosphoinositide 3-kinase (PI3K)/AKT/phosphatase and tensin homologue (PTEN) pathway alteration status of tumours, as ascertained using assays available at the time. Here, we report updated progression-free survival and overall survival results, and a prespecified examination of the effect of PI3K/AKT/PTEN pathway alterations identified by an expanded genetic testing panel on treatment outcomes. METHODS: This randomised, multicentre, double-blind, placebo-controlled, phase 2 trial recruited postmenopausal adult women aged at least 18 years with ER-positive, HER2-negative, metastatic or locally advanced inoperable breast cancer and an Eastern Cooperative Oncology Group performance status of 0-2, who had relapsed or progressed on an aromatase inhibitor, from across 19 hospitals in the UK. Participants were randomly assigned (1:1) to receive intramuscular fulvestrant 500 mg (day 1) every 28 days (plus a 500 mg loading dose on day 15 of cycle 1) with either capivasertib 400 mg or matching placebo, orally twice daily on an intermittent weekly schedule of 4 days on and 3 days off, starting on cycle 1 day 15. Treatment continued until disease progression, unacceptable toxicity, loss to follow-up, or withdrawal of consent. Treatment was allocated by an interactive web-response system using a minimisation method (with a 20% random element) and the following minimisation factors: measurable or non-measurable disease, primary or secondary aromatase inhibitor resistance, PIK3CA status, and PTEN status. The primary endpoint was progression-free survival in the intention-to-treat population. Secondary endpoints shown in this Article were overall survival and safety in the intention-to-treat population, and the effect of tumour PI3K/AKT/PTEN pathway status identified by an expanded testing panel that included next-generation sequencing assays. Recruitment is complete. The trial is registered with ClinicalTrials.gov, number NCT01992952. FINDINGS: Between March 16, 2015, and March 6, 2018, 183 participants were screened for eligibility and 140 (77%) were randomly assigned to receive fulvestrant plus capivasertib (n=69) or fulvestrant plus placebo (n=71). Median follow-up at the data cut-off of Nov 25, 2021, was 58·5 months (IQR 45·9-64·1) for participants treated with fulvestrant plus capivasertib and 62·3 months (IQR 62·1-70·3) for fulvestrant plus placebo. Updated median progression-free survival was 10·3 months (95% CI 5·0-13·4) in the group receiving fulvestrant plus capivasertib compared with 4·8 months (3·1-7·9) for fulvestrant plus placebo (adjusted hazard ratio [HR] 0·56 [95% CI 0·38-0·81]; two-sided p=0·0023). Median overall survival in the capivasertib versus placebo groups was 29·3 months (95% CI 23·7-39·0) versus 23·4 months (18·7-32·7; adjusted HR 0·66 [95% CI 0·45-0·97]; two-sided p=0·035). The expanded biomarker panel identified an expanded pathway-altered subgroup that contained 76 participants (54% of the intention-to-treat population). Median progression-free survival in the expanded pathway-altered subgroup for participants receiving capivasertib (n=39) was 12·8 months (95% CI 6·6-18·8) compared with 4·6 months (2·8-7·9) in the placebo group (n=37; adjusted HR 0·44 [95% CI 0·26-0·72]; two-sided p=0·0014). Median overall survival for the expanded pathway-altered subgroup receiving capivasertib was 38·9 months (95% CI 23·3-50·7) compared with 20·0 months (14·8-31·4) for those receiving placebo (adjusted HR 0·46 [95% CI 0·27-0·79]; two-sided p=0·0047). By contrast, there were no statistically significant differences in progression-free or overall survival in the expanded pathway non-altered subgroup treated with capivasertib (n=30) versus placebo (n=34). One additional serious adverse event (pneumonia) in the capivasertib group had occurred subsequent to the primary analysis. One death, due to atypical pulmonary infection, was assessed as possibly related to capivasertib treatment. INTERPRETATION: Updated FAKTION data showed that capivasertib addition to fulvestrant extends the survival of participants with aromatase inhibitor-resistant ER-positive, HER2-negative advanced breast cancer. The expanded biomarker testing suggested that capivasertib predominantly benefits patients with PI3K/AKT/PTEN pathway-altered tumours. Phase 3 data are needed to substantiate the results, including in patients with previous CDK4/6 inhibitor exposure who were not included in the FAKTION trial. FUNDING: AstraZeneca and Cancer Research UK.

Fulvestrant plus capivasertib versus placebo after relapse or progression on an aromatase inhibitor in metastatic, oestrogen receptor-positive breast cancer (FAKTION): a multicentre, randomised, controlled, phase 2 trial.

BACKGROUND: Capivasertib (AZD5363) is a potent selective oral inhibitor of all three isoforms of the serine/threonine kinase AKT. The FAKTION trial investigated whether the addition of capivasertib to fulvestrant improved progression-free survival in patients with aromatase inhibitor-resistant advanced breast cancer. METHODS: In this randomised, double-blind, placebo-controlled, phase 2 trial, postmenopausal women aged at least 18 years with an Eastern Cooperative Oncology Group performance status of 0-2 and oestrogen receptor-positive, HER2-negative, metastatic or locally advanced inoperable breast cancer who had relapsed or progressed on an aromatase inhibitor were recruited from 19 hospitals in the UK. Enrolled participants were randomly assigned (1:1) to receive intramuscular fulvestrant 500 mg (day 1) every 28 days (plus a loading dose on day 15 of cycle 1) with either capivasertib 400 mg or matching placebo, orally twice daily on an intermittent weekly schedule of 4 days on and 3 days off (starting on cycle 1 day 15) until disease progression, unacceptable toxicity, loss to follow-up, or withdrawal of consent. Treatment allocation was done using an interactive web-response system using a minimisation method (with a 20% random element) and the following minimisation factors: measurable or non-measurable disease, primary or secondary aromatase inhibitor resistance, PIK3CA status, and PTEN status. The primary endpoint was progression-free survival with a one-sided alpha of 0·20. Analyses were done by intention to treat. Recruitment is complete, and the trial is in follow-up. This trial is registered with ClinicalTrials.gov, number NCT01992952. FINDINGS: Between March 16, 2015, and March 6, 2018, 183 patients were screened for eligibility, of whom 140 (76%) were eligible and were randomly assigned to receive fulvestrant plus capivasertib (n=69) or fulvestrant plus placebo (n=71). Median follow-up for progression-free survival was 4·9 months (IQR 1·6-11·6). At the time of primary analysis for progression-free survival (Jan 30, 2019), 112 progression-free survival events had occurred, 49 (71%) in 69 patients in the capivasertib group compared with 63 (89%) of 71 in the placebo group. Median progression-free survival was 10·3 months (95% CI 5·0-13·2) in the capivasertib group versus 4·8 months (3·1-7·7) in the placebo group, giving an unadjusted hazard ratio (HR) of 0·58 (95% CI 0·39-0·84) in favour of the capivasertib group (two-sided p=0·0044; one-sided log rank test p=0·0018). The most common grade 3-4 adverse events were hypertension (22 [32%] of 69 patients in the capivasertib group vs 17 [24%] of 71 in the placebo group), diarrhoea (ten [14%] vs three [4%]), rash (14 [20%] vs 0), infection (four [6%] vs two [3%]), and fatigue (one [1%] vs three [4%]). Serious adverse reactions occurred only in the capivasertib group, and were acute kidney injury (two), diarrhoea (three), rash (two), hyperglycaemia (one), loss of consciousness (one), sepsis (one), and vomiting (one). One death, due to atypical pulmonary infection, was assessed as possibly related to capivasertib treatment. One further death in the capivasertib group had an unknown cause; all remaining deaths in both groups (19 in the capivasertib group and 31 in the placebo group) were disease related. INTERPRETATION: Progression-free survival was significantly longer in participants who received capivasertib than in those who received placebo. The combination of capivasertib and fulvestrant warrants further investigation in phase 3 trials. FUNDING: AstraZeneca and Cancer Research UK.

Coronary-Artery Bypass Surgery in Patients with Ischemic Cardiomyopathy.

BACKGROUND: The survival benefit of a strategy of coronary-artery bypass grafting (CABG) added to guideline-directed medical therapy, as compared with medical therapy alone, in patients with coronary artery disease, heart failure, and severe left ventricular systolic dysfunction remains unclear. METHODS: From July 2002 to May 2007, a total of 1212 patients with an ejection fraction of 35% or less and coronary artery disease amenable to CABG were randomly assigned to undergo CABG plus medical therapy (CABG group, 610 patients) or medical therapy alone (medical-therapy group, 602 patients). The primary outcome was death from any cause. Major secondary outcomes included death from cardiovascular causes and death from any cause or hospitalization for cardiovascular causes. The median duration of follow-up, including the current extended-follow-up study, was 9.8 years. RESULTS: A primary outcome event occurred in 359 patients (58.9%) in the CABG group and in 398 patients (66.1%) in the medical-therapy group (hazard ratio with CABG vs. medical therapy, 0.84; 95% confidence interval [CI], 0.73 to 0.97; P=0.02 by log-rank test). A total of 247 patients (40.5%) in the CABG group and 297 patients (49.3%) in the medical-therapy group died from cardiovascular causes (hazard ratio, 0.79; 95% CI, 0.66 to 0.93; P=0.006 by log-rank test). Death from any cause or hospitalization for cardiovascular causes occurred in 467 patients (76.6%) in the CABG group and in 524 patients (87.0%) in the medical-therapy group (hazard ratio, 0.72; 95% CI, 0.64 to 0.82; P<0.001 by log-rank test). CONCLUSIONS: In a cohort of patients with ischemic cardiomyopathy, the rates of death from any cause, death from cardiovascular causes, and death from any cause or hospitalization for cardiovascular causes were significantly lower over 10 years among patients who underwent CABG in addition to receiving medical therapy than among those who received medical therapy alone. (Funded by the National Institutes of Health; STICH [and STICHES] ClinicalTrials.gov number, NCT00023595.).

The variable position of the inferior alveolar nerve (IAN) in the mandibular ramus: a computed tomography (CT) study.

INTRODUCTION: This study was designed to quantify the important anatomical landmarks and the path of the inferior alveolar nerve (IAN) within the human mandibular body and ramus, in particular with reference to the bilateral sagittal split osteotomy (BSSO). MATERIALS AND METHODS: Four hundred and eleven CT scans were studied, 299 of these were involved in determining the position of lingula; and 230 were involved in determining the course of IAN in the mandibular molar region, namely from the mesial of the mandibular first molar to the distal of the mandibular second molar; 118 were involved with both measurements. RESULTS: On average, the lingula was located 17.0 ± 2.2 mm from the external oblique ridge; 11.6 ± 2.0 mm from the internal oblique ridge; 17.2 ± 2.7 mm from the sigmoid notch; and 15.6 ± 1.9 mm from the posterior border of the mandible. The course of the IAN in the mandibular molar region was found to descend vertically from the distal of the mandibular second molar (7) to reach its lowest point between the first and second molars (6 and 7), and then ascend towards the mesial of the first molar (6). Horizontally, the IAN was found to traverse medially between the distal of the 7 and the middle of the 7, and then changes its path laterally towards the mesial of the 6. CONCLUSION: Precise knowledge of the individual's position of the IAN will help surgical planning.

Influence of Baseline Characteristics, Operative Conduct, and Postoperative Course on 30-Day Outcomes of Coronary Artery Bypass Grafting Among Patients With Left Ventricular Dysfunction: Results From the Surgical Treatment for Ischemic Heart Failure (STICH) Trial.

BACKGROUND: Patients with severe left ventricular dysfunction, ischemic heart failure, and coronary artery disease suitable for coronary artery bypass grafting (CABG) are at higher risk for surgical morbidity and mortality. Paradoxically, those patients with the most severe coronary artery disease and ventricular dysfunction who derive the greatest clinical benefit from CABG are also at the greatest operative risk, which makes decision making regarding whether to proceed to surgery difficult in such patients. To better inform such decision making, we analyzed the Surgical Treatment for Ischemic Heart Failure (STICH) CABG population for detailed information on perioperative risk and outcomes. METHODS AND RESULTS: In both STICH trials (hypotheses), 2136 patients with a left ventricular ejection fraction of ≤35% and coronary artery disease were allocated to medical therapy, CABG plus medical therapy, or CABG with surgical ventricular reconstruction. Relationships of baseline characteristics and operative conduct with morbidity and mortality at 30 days were evaluated. There were a total of 1460 patients randomized to and receiving surgery, and 346 (≈25%) of these high-risk patients developed a severe complication within 30 days. Worsening renal insufficiency, cardiac arrest with cardiopulmonary resuscitation, and ventricular arrhythmias were the most frequent complications and those most commonly associated with death. Mortality at 30 days was 5.1% and was generally preceded by a serious complication (65 of 74 deaths). Left ventricular size, renal dysfunction, advanced age, and atrial fibrillation/flutter were significant preoperative predictors of mortality within 30 days. Cardiopulmonary bypass time was the only independent surgical variable predictive of 30-day mortality. CONCLUSIONS: CABG can be performed with relatively low 30-day mortality in patients with left ventricular dysfunction. Serious postoperative complications occurred in nearly 1 in 4 patients and were associated with mortality. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT00023595.

Coronary-artery bypass surgery in patients with left ventricular dysfunction.

BACKGROUND: The role of coronary-artery bypass grafting (CABG) in the treatment of patients with coronary artery disease and heart failure has not been clearly established. METHODS: Between July 2002 and May 2007, a total of 1212 patients with an ejection fraction of 35% or less and coronary artery disease amenable to CABG were randomly assigned to medical therapy alone (602 patients) or medical therapy plus CABG (610 patients). The primary outcome was the rate of death from any cause. Major secondary outcomes included the rates of death from cardiovascular causes and of death from any cause or hospitalization for cardiovascular causes. RESULTS: The primary outcome occurred in 244 patients (41%) in the medical-therapy group and 218 (36%) in the CABG group (hazard ratio with CABG, 0.86; 95% confidence interval [CI], 0.72 to 1.04; P=0.12). A total of 201 patients (33%) in the medical-therapy group and 168 (28%) in the CABG group died from an adjudicated cardiovascular cause (hazard ratio with CABG, 0.81; 95% CI, 0.66 to 1.00; P=0.05). Death from any cause or hospitalization for cardiovascular causes occurred in 411 patients (68%) in the medical-therapy group and 351 (58%) in the CABG group (hazard ratio with CABG, 0.74; 95% CI, 0.64 to 0.85; P<0.001). By the end of the follow-up period (median, 56 months), 100 patients in the medical-therapy group (17%) underwent CABG, and 555 patients in the CABG group (91%) underwent CABG. CONCLUSIONS: In this randomized trial, there was no significant difference between medical therapy alone and medical therapy plus CABG with respect to the primary end point of death from any cause. Patients assigned to CABG, as compared with those assigned to medical therapy alone, had lower rates of death from cardiovascular causes and of death from any cause or hospitalization for cardiovascular causes. (Funded by the National Heart, Lung, and Blood Institute and Abbott Laboratories; STICH ClinicalTrials.gov number, NCT00023595.).

Myocardial viability and survival in ischemic left ventricular dysfunction.

BACKGROUND: The assessment of myocardial viability has been used to identify patients with coronary artery disease and left ventricular dysfunction in whom coronary-artery bypass grafting (CABG) will provide a survival benefit. However, the efficacy of this approach is uncertain. METHODS: In a substudy of patients with coronary artery disease and left ventricular dysfunction who were enrolled in a randomized trial of medical therapy with or without CABG, we used single-photon-emission computed tomography (SPECT), dobutamine echocardiography, or both to assess myocardial viability on the basis of prespecified thresholds. RESULTS: Among the 1212 patients enrolled in the randomized trial, 601 underwent assessment of myocardial viability. Of these patients, we randomly assigned 298 to receive medical therapy plus CABG and 303 to receive medical therapy alone. A total of 178 of 487 patients with viable myocardium (37%) and 58 of 114 patients without viable myocardium (51%) died (hazard ratio for death among patients with viable myocardium, 0.64; 95% confidence interval [CI], 0.48 to 0.86; P=0.003). However, after adjustment for other baseline variables, this association with mortality was not significant (P=0.21). There was no significant interaction between viability status and treatment assignment with respect to mortality (P=0.53). CONCLUSIONS: The presence of viable myocardium was associated with a greater likelihood of survival in patients with coronary artery disease and left ventricular dysfunction, but this relationship was not significant after adjustment for other baseline variables. The assessment of myocardial viability did not identify patients with a differential survival benefit from CABG, as compared with medical therapy alone. (Funded by the National Heart, Lung, and Blood Institute; STICH ClinicalTrials.gov number, NCT00023595.).

Influence of mitral regurgitation repair on survival in the surgical treatment for ischemic heart failure trial.

BACKGROUND: Whether mitral valve repair during coronary artery bypass grafting (CABG) improves survival in patients with ischemic mitral regurgitation (MR) remains unknown. METHODS AND RESULTS: Patients with ejection fraction ≤35% and coronary artery disease amenable to CABG were randomized at 99 sites worldwide to medical therapy with or without CABG. The decision to treat the mitral valve during CABG was left to the surgeon. The primary end point was mortality. Of 1212 randomized patients, 435 (36%) had none/trace MR, 554 (46%) had mild MR, 181 (15%) had moderate MR, and 39 (3%) had severe MR. In the medical arm, 70 deaths (32%) occurred in patients with none/trace MR, 114 (44%) in those with mild MR, and 58 (50%) in those with moderate to severe MR. In patients with moderate to severe MR, there were 29 deaths (53%) among 55 patients randomized to CABG who did not receive mitral surgery (hazard ratio versus medical therapy, 1.20; 95% confidence interval, 0.77-1.87) and 21 deaths (43%) among 49 patients who received mitral surgery (hazard ratio versus medical therapy, 0.62; 95% confidence interval, 0.35-1.08). After adjustment for baseline prognostic variables, the hazard ratio for CABG with mitral surgery versus CABG alone was 0.41 (95% confidence interval, 0.22-0.77; P=0.006). CONCLUSION: Although these observational data suggest that adding mitral valve repair to CABG in patients with left ventricular dysfunction and moderate to severe MR may improve survival compared with CABG alone or medical therapy alone, a prospective randomized trial is necessary to confirm the validity of these observations. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT00023595.

Immune cell status, cardiorespiratory fitness and body composition among breast cancer survivors and healthy women: a cross sectional study.

Methods: We examined whether immune cell profiles differ between healthy women (n = 38) and breast cancer survivors (n = 27) within 2 years of treatment, and whether any group-differences were influenced by age, cytomegalovirus infection, cardiorespiratory fitness and body composition. Using flow cytometry, CD4+ and CD8+ T cell subsets, including naïve (NA), central memory (CM) and effector cells (EM and EMRA) were identified using CD27/CD45RA. Activation was measured by HLA-DR expression. Stem cell-like memory T cells (TSCMs) were identified using CD95/CD127. B cells, including plasmablasts, memory, immature and naïve cells were identified using CD19/CD27/CD38/CD10. Effector and regulatory Natural Killer cells were identified using CD56/CD16. Results: Compared to healthy women, CD4+ CM were +Δ21% higher among survivors (p = 0.028) and CD8+ NA were -Δ25% lower (p = 0.034). Across CD4+ and CD8+ subsets, the proportion of activated (HLA-DR+) cells was +Δ31% higher among survivors: CD4+ CM (+Δ25%), CD4+ EM (+Δ32%) and CD4+ EMRA (+Δ43%), total CD8+ (+Δ30%), CD8+ EM (+Δ30%) and CD8+ EMRA (+Δ25%) (p < 0.046). The counts of immature B cells, NK cells and CD16+ NK effector cells were higher among survivors (+Δ100%, +Δ108% and +Δ143% respectively, p < 0.04). Subsequent analyses examined whether statistically significant differences in participant characteristics, influenced immunological differences between groups. Compared to healthy women, survivors were older (56 ± 6 y vs. 45 ± 11 y), had lower cardiorespiratory fitness (V˙O2max mL kg-1 min-1: 28.8 ± 5.0 vs. 36.2 ± 8.5), lower lean mass (42.3 ± 5.0 kg vs. 48.4 ± 15.8 kg), higher body fat (36.3% ± 5.3% vs. 32.7% ± 6.4%) and higher fat mass index (FMI kg/m2: 9.5 ± 2.2 vs. 8.1 ± 2.7) (all p < 0.033). Analysis of covariance revealed divergent moderating effects of age, CMV serostatus, cardiorespiratory fitness and body composition on the differences in immune cell profiles between groups, depending on the cell type examined. Moreover, across all participants, fat mass index was positively associated with the proportion of HLA-DR+ CD4+ EMRA and CD8+ EM/EMRA T cells (Pearson correlation: r > 0.305, p < 0.019). The association between fat mass index and HLA-DR+ CD8+ EMRA T cells withstood statistical adjustment for all variables, including age, CMV serostatus, lean mass and cardiorespiratory fitness, potentially implicating these cells as contributors to inflammatory/immune-dysfunction in overweight/obesity.

Coronary bypass surgery with or without surgical ventricular reconstruction.

BACKGROUND: Surgical ventricular reconstruction is a specific procedure designed to reduce left ventricular volume in patients with heart failure caused by coronary artery disease. We conducted a trial to address the question of whether surgical ventricular reconstruction added to coronary-artery bypass grafting (CABG) would decrease the rate of death or hospitalization for cardiac causes, as compared with CABG alone. METHODS: Between September 2002 and January 2006, a total of 1000 patients with an ejection fraction of 35% or less, coronary artery disease that was amenable to CABG, and dominant anterior left ventricular dysfunction that was amenable to surgical ventricular reconstruction were randomly assigned to undergo either CABG alone (499 patients) or CABG with surgical ventricular reconstruction (501 patients). The primary outcome was a composite of death from any cause and hospitalization for cardiac causes. The median follow-up was 48 months. RESULTS: Surgical ventricular reconstruction reduced the end-systolic volume index by 19%, as compared with a reduction of 6% with CABG alone. Cardiac symptoms and exercise tolerance improved from baseline to a similar degree in the two study groups. However, no significant difference was observed in the primary outcome, which occurred in 292 patients (59%) who were assigned to undergo CABG alone and in 289 patients (58%) who were assigned to undergo CABG with surgical ventricular reconstruction (hazard ratio for the combined approach, 0.99; 95% confidence interval, 0.84 to 1.17; P=0.90). CONCLUSIONS: Adding surgical ventricular reconstruction to CABG reduced the left ventricular volume, as compared with CABG alone. However, this anatomical change was not associated with a greater improvement in symptoms or exercise tolerance or with a reduction in the rate of death or hospitalization for cardiac causes. (ClinicalTrials.gov number, NCT00023595.)

Compositional stability and diversity of vascular plant communities following logging disturbance in Appalachian forests.

Human-caused changes in disturbance regimes and introductions of nonnative species have the potential to result in widespread, directional changes in forest community structure. The degree that plant community composition persists or changes following disturbances depends on the balance between local extirpation and colonization by new species, including nonnatives. In this study, we examined species losses and gains, and entry of native vs. exotic species to determine how oak forests in the Appalachian Mountains might shift in species composition following a gradient of pulse disturbances (timber harvesting). We asked (1) how compositional stability of the plant community (resistance and resilience) was influenced by disturbance intensity, (2) whether community responses were driven by extirpation or colonization of species, and (3) how disturbance intensity influenced total and functional group diversity, including the nonnative proportion of the flora through time. We collected data at three spatial scales and three times, including just before, one year post-disturbance, and 10 years post-disturbance. Resistance was estimated using community distance measures between pre- and one year post-disturbance, and resilience using community distance between pre- and 10-year post-disturbance conditions. The number of colonizing and extirpated species between sampling times was analyzed for all species combined and for six functional groups. Resistance and resilience decreased with increasing timber-harvesting disturbance; compositional stability was lower in the most disturbed plots, which was driven by colonization, but not extirpation, of species. Colonization of species also led to increases in diversity after disturbance that was typically maintained after 10 years following disturbance. Most of the community-level responses were driven by post-disturbance colonization of native forbs and graminoids. The nonnative proportion of plant species tended to increase following disturbance, especially at large spatial scales in the most disturbed treatments, but tended to decrease through time following disturbance due to canopy development. The results of this study are consistent with the theory that resources released by disturbance have strong influences on species colonization and community composition. The effects of management activities tested in this study, which span a gradient of timber-harvesting disturbance, shift species composition largely via an increase in species colonization and diversity.

Drug-eluting stents vs. coronary-artery bypass grafting in multivessel coronary disease.

BACKGROUND: Numerous studies have compared the outcomes of two competing interventions for multivessel coronary artery disease: coronary-artery bypass grafting (CABG) and coronary stenting. However, little information has become available since the introduction of drug-eluting stents. METHODS: We identified patients with multivessel disease who received drug-eluting stents or underwent CABG in New York State between October 1, 2003, and December 31, 2004, and we compared adverse outcomes (death, death or myocardial infarction, or repeat revascularization) through December 31, 2005, after adjustment for differences in baseline risk factors among the patients. RESULTS: In comparison with treatment with a drug-eluting stent, CABG was associated with lower 18-month rates of death and of death or myocardial infarction both for patients with three-vessel disease and for patients with two-vessel disease. Among patients with three-vessel disease who underwent CABG, as compared with those who received a stent, the adjusted hazard ratio for death was 0.80 (95% confidence interval [CI], 0.65 to 0.97) and the adjusted survival rate was 94.0% versus 92.7% (P=0.03); the adjusted hazard ratio for death or myocardial infarction was 0.75 (95% CI, 0.63 to 0.89) and the adjusted rate of survival free from myocardial infarction was 92.1% versus 89.7% (P<0.001). Among patients with two-vessel disease who underwent CABG, as compared with those who received a stent, the adjusted hazard ratio for death was 0.71 (95% CI, 0.57 to 0.89) and the adjusted survival rate was 96.0% versus 94.6% (P=0.003); the adjusted hazard ratio for death or myocardial infarction was 0.71 (95% CI, 0.59 to 0.87) and the adjusted rate of survival free from myocardial infarction was 94.5% versus 92.5% (P<0.001). Patients undergoing CABG also had lower rates of repeat revascularization. CONCLUSIONS: For patients with multivessel disease, CABG continues to be associated with lower mortality rates than does treatment with drug-eluting stents and is also associated with lower rates of death or myocardial infarction and repeat revascularization.

Psychogeriatric inpatient unit design: a literature review.

BACKGROUND: In many parts of the world the provision of psychogeriatric inpatient units (PGUs) remains limited. More units will be required over coming decades given rapid population aging. METHODS: Medline (1950-2010), psycINFO (1806-2009), EMBASE (1980-2009) and CINAHL (1982-2009) were searched for papers about PGU design. Selected non-peer reviewed literature such as government reports and unpublished academic dissertations were also reviewed. Data were also obtained from the literature related to general adult psychiatry inpatient units where there was limited information from studies of units designed for older people. Over 200 papers were reviewed and 130 were included. RESULTS: There are few good quality studies to guide the design of acute PGUs and much of the existing literature is based on opinion and anecdote or, at best, based on observational studies. Randomized controlled studies comparing different designs and assessing outcomes are virtually non-existent. Several studies have identified violence and trauma resulting from hospitalization as significant problems with current acute PGU care. Despite its limitations the available literature provides useful guidance on how PGU design can optimize patient and staff safety and improve clinical outcomes. CONCLUSIONS: There are significant problems with current acute PGUs, and patient mix on existing units is an important issue. Future research should examine patient and staff perceptions of different PGU ward environments, the relationship between ward design and clinical outcomes, the effects of segregating patients with challenging behaviors in dementia and the benefits or otherwise of gender segregation.

A Phenomic Perspective on Factors Influencing Breast Cancer Treatment: Integrating Aging and Lifestyle in Blood and Tissue Biomarker Profiling.

Breast cancer is the most common malignancy among women worldwide. Over the last four decades, diagnostic and therapeutic procedures have improved substantially, giving patients with localized disease a better chance of cure, and those with more advanced cancer, longer periods of disease control and survival. However, understanding and managing heterogeneity in the clinical response exhibited by patients remains a challenge. For some treatments, biomarkers are available to inform therapeutic options, assess pathological response and predict clinical outcomes. Nevertheless, some measurements are not employed universally and lack sensitivity and specificity, which might be influenced by tissue-specific alterations associated with aging and lifestyle. The first part of this article summarizes available and emerging biomarkers for clinical use, such as measurements that can be made in tumor biopsies or blood samples, including so-called liquid biopsies. The second part of this article outlines underappreciated factors that could influence the interpretation of these clinical measurements and affect treatment outcomes. For example, it has been shown that both adiposity and physical activity can modify the characteristics of tumors and surrounding tissues. In addition, evidence shows that inflammaging and immunosenescence interact with treatment and clinical outcomes and could be considered prognostic and predictive factors independently. In summary, changes to blood and tissues that reflect aging and patient characteristics, including lifestyle, are not commonly considered clinically or in research, either for practical reasons or because the supporting evidence base is developing. Thus, an aim of this article is to encourage an integrative phenomic approach in oncology research and clinical management.

Comparison of coronary artery stenting outcomes in the eras before and after the introduction of drug-eluting stents.

BACKGROUND: Few studies have compared medium-term outcomes for drug-eluting stents (DES) and bare metal stents, and most are relatively small randomized controlled trials. Furthermore, since the introduction of DES, there has been increased use and duration of use of clopidogrel, statins, and other evidence-based therapies. The purpose of the present study was to compare outcomes for patients who underwent stenting in the eras before and after the introduction of DES. METHODS AND RESULTS: New York state patients undergoing stenting in all nonfederal hospitals in the state were studied. Patients were excluded if they had a previous revascularization. Risk factors that were significant predictors of adverse outcomes were used to adjust adverse outcome rates. The study included 11,436 patients who received stents between October 1, 2002, and March 31, 2003, and 12,926 patients who underwent stenting between October 1, 2003, and March 31, 2004. Death rates, the combined end point of death and myocardial infarction (MI), nonfatal MI requiring readmission, target vessel revascularization, and target lesion revascularization were compared at 2 years. Patients in the DES era had significantly better risk-adjusted outcomes for death/MI (adjusted hazard ratio, 0.90; 95% confidence interval, 0.83 to 0.97), 9.9% versus 10.8%; nonfatal MI requiring readmission (adjusted hazard ratio, 0.86; 95% confidence interval, 0.76 to 0.97); target vessel revascularization (adjusted hazard ratio, 0.60; 95% confidence interval, 0.56 to 0.64), 11.2% versus 17.9%; and target lesion revascularization (hazard ratio, 0.55; 95% confidence interval, 0.51 to 0.59), 8.4% versus 14.7%. CONCLUSIONS: Patients in the DES era experienced lower rates of death/MI, nonfatal MI, target vessel revascularization, and target lesion revascularization, but there were no differences in the rates of death. These improvements are likely a result of increased use of clopidogrel, statins, and dual antiplatelet therapy, in addition to the introduction of DES.

Disturbance alters local-regional richness relationships in Appalachian forests.

Whether biological diversity within communities is limited by local interactions or regional species pools remains an important question in ecology. In this paper, we investigate how an experimentally applied tree-harvesting disturbance gradient influenced local-regional richness relationships. Plant species richness was measured at three spatial scales (2 ha = regional; 576 m2 and 1 m2 = local) on three occasions (one year pre-disturbance, one year post-disturbance, and 10 years post-disturbance) across five disturbance treatments (uncut control through clearcut) replicated throughout the southern Appalachian Mountains, USA. We investigated whether species richness in 576-m2 plots and 1-m2 subplots depended on species richness in 2-ha experimental units and whether this relationship changed through time before and after canopy disturbance. We found that, before disturbance, the relationship between local and regional richness was weak or nonexistent. One year after disturbance local richness was a positive function of regional richness, because local sites were colonized from the regional species pool. Ten years after disturbance, the positive relationship persisted, but the slope had decreased by half. These results suggest that disturbance can set the stage for strong influences of regional species pools on local community assembly in temperate forests. However, as time since disturbance increases, local controls on community assembly decouple the relationships between regional and local diversity.

An evaluation of the effectiveness of a case-specific approach to challenging behaviour associated with dementia.

OBJECTIVES: Treatment of challenging behaviour in dementia using standardized psychopharmacological or psychosocial approaches remains problematical. A case-specific approach was trialled in this study, based on extensive evidence that each case is different in aetiology, the effects of the behaviour on others and what interventions are possible given the available resources. METHOD: Forty-four consecutive referrals for challenging behaviour (two-thirds in residential care) were assessed across multiple causal domains. Both assessment and development of interventions were undertaken in collaboration with family carers and care staff. Measures of behaviour and associated carer distress, as well as medication and service use, were taken pre-intervention and at 2- and 5-month follow-ups. RESULTS: Psychotropic medication was used with a minority of participants but, overall, antipsychotic use was reduced. Psychosocial methods predominated, with 77% of cases judged as mainly or entirely psychosocial by an expert panel. There were significant mean improvements in behaviour and carer distress. Using conservative criteria there was a 65.9% clinical success rate. CONCLUSION: Results confirm those of other studies which have used multifaceted interventions tailored to the unique needs of each case. They compare favourably with results from trials of standardized psycho-pharmacological or psychosocial approaches. More trials are needed, necessarily involving further development of robust methodologies which reflect the case-specific nature of challenging behaviour associated with dementia.