Lapatinib (L) plus trastuzumab (T) improves outcomes for metastatic human epidermal growth factor 2-positive breast cancer and increases the pathologic complete response in the neoadjuvant setting, ...but their role as adjuvant therapy remains uncertain.
In the Adjuvant Lapatinib and/or Trastuzumab Treatment Optimization trial, patients with centrally confirmed human epidermal growth factor 2-positive early breast cancer were randomly assigned to 1 year of adjuvant therapy with T, L, their sequence (T→L), or their combination (L+T). The primary end point was disease-free survival (DFS), with 850 events required for 80% power to detect a hazard ratio (HR) of 0.8 for L+T versus T.
Between June 2007 and July 2011, 8,381 patients were enrolled. In 2011, due to futility to demonstrate noninferiority of L versus T, the L arm was closed, and patients free of disease were offered adjuvant T. A protocol modification required P ≤ .025 for the two remaining pairwise comparisons. At a protocol-specified analysis with a median follow-up of 4.5 years, a 16% reduction in the DFS hazard rate was observed with L+T compared with T (555 DFS events; HR, 0.84; 97.5% CI, 0.70 to 1.02; P = .048), and a 4% reduction was observed with T→L compared with T (HR, 0.96; 97.5% CI, 0.80 to 1.15; P = .61). L-treated patients experienced more diarrhea, cutaneous rash, and hepatic toxicity compared with T-treated patients. The incidence of cardiac toxicity was low in all treatment arms.
Adjuvant treatment that includes L did not significantly improve DFS compared with T alone and added toxicity. One year of adjuvant T remains standard of care.
A combination of Pd2(dba)3 and SPhos (1:2 molar ratio) is an excellent precatalyst for the Negishi cross-coupling of the serine-derived organozinc reagent 2 with aryl halides, including previously ...difficult ortho-substituted examples. In the case of meta- and para-substituted aryl halides, Pd-loadings of 0.5 mol % give satisfactory results. Use of 2-iodoaniline as substrate gives the lactam 12 in good yield.
Centrosome amplification (CA) is a common phenomenon in cancer, promotes genomic stability and cancer evolution, and has been reported to promote metastasis. CA promotes a stochastic gain/loss of ...chromosomes during cell division, known as chromosomal instability (CIN). However, it is unclear whether CA is present in circulating tumor cells (CTCs), the seeds for metastasis. Here, we surveyed CA in CTCs from human subjects with metastatic breast cancer. CTCs were captured by CD45 exclusion and selection of EpCAM‐positive cells using an exclusion‐based sample preparation technology platform known as VERSA (versatile exclusion‐based rare sample analysis). Centriole amplification (centrin foci> 4) is the definitive assay for CA. However, determination of centrin foci is technically challenging and incompatible with automated analysis. To test if the more technically accessible centrosome marker pericentrin could serve as a surrogate for centriole amplification in CTCs, cells were stained with pericentrin and centrin antibodies to evaluate CA. This assay was first validated using breast cancer cell lines and a nontransformed epithelial cell line model of inducible CA, then translated to CTCs. Pericentrin area and pericentrin area x intensity correlate well with centrin foci, validating pericentrin as a surrogate marker of CA. CA is found in CTCs from 75% of subjects, with variability in the percentage and extent of CA in individual circulating cells in a given subject, similar to the variability previously seen in primary tumors and cell lines. In summary, we created, validated, and implemented a novel method to assess CA in CTCs from subjects with metastatic breast cancer. Such an assay will be useful for longitudinal monitoring of CA in cancer patients and in prospective clinical trials for assessing the impact of CA on response to therapy.
Circulating tumor cells (CTCs) are a rare population of cancer cells released into peripheral circulation from primary and metastatic cancer sites. Centrosome amplification (CA) has been reported in virtually all human cancers and has been shown to make cells more invasive. In this study, we develop an assay to detect CA in CTCs. We find that CA is prevalent in CTCs from subjects with metastatic breast cancer.
A pharmacologic approach to male contraception remains a longstanding challenge in medicine. Toward this objective, we explored the spermatogenic effects of a selective small-molecule inhibitor (JQ1) ...of the bromodomain and extraterminal (BET) subfamily of epigenetic reader proteins. Here, we report potent inhibition of the testis-specific member BRDT, which is essential for chromatin remodeling during spermatogenesis. Biochemical and crystallographic studies confirm that occupancy of the BRDT acetyl-lysine binding pocket by JQ1 prevents recognition of acetylated histone H4. Treatment of mice with JQ1 reduced seminiferous tubule area, testis size, and spermatozoa number and motility without affecting hormone levels. Although JQ1-treated males mate normally, inhibitory effects of JQ1 evident at the spermatocyte and round spermatid stages cause a complete and reversible contraceptive effect. These data establish a new contraceptive that can cross the blood:testis boundary and inhibit bromodomain activity during spermatogenesis, providing a lead compound targeting the male germ cell for contraception.
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► Bromodomain, testis-specific (BRDT) is a contraceptive target ► JQ1 is a BRDT inhibitor that causes a reversible contraceptive effect in male mice ► JQ1 alters spermatogenesis at the spermatocyte and round spermatid stages ► JQ1 treatment targets the male germline and reduces spermatozoa number and motility
Inhibition of the chromatin reader protein BRDT with the small molecule JQ1 provides an approach for reversible male contraception.
The American Heart Association/American Stroke Association released the adult stroke rehabilitation and recovery guidelines in 2016. A working group of stroke rehabilitation experts reviewed these ...guidelines and identified a subset of recommendations that were deemed suitable for creating performance measures. These 13 performance measures are reported here and contain inclusion and exclusion criteria to allow calculation of rates of compliance in a variety of settings ranging from acute hospital care to postacute care and care in the home and outpatient setting.
Abstract
BACKGROUND
Resection is a critical component in the initial treatment of glioblastoma (GBM). Often GBMs are resected using an intralesional method. Circumferential perilesional resection of ...GBMs has been described, but with limited data.
OBJECTIVE
To conduct an observational retrospective analysis to test whether perilesional resection produced a greater extent of resection.
METHODS
We identified all patients with newly diagnosed GBM who underwent resection at our institution from June 1, 1993 to December 31, 2015. Demographics, presenting symptoms, intraoperative data, method of resection (perilesional or intralesional), volumetric imaging data, and postoperative outcomes were obtained. Complete resection (CR) was defined as 100% resection of all contrast-enhancing disease. Univariate analyses employed analysis of variance (ANOVA) and Fisher's exact test. Multivariate analyses used propensity score-weighted multivariate logistic regression.
RESULTS
Newly diagnosed GBMs were resected in 1204 patients, 436 tumors (36%) perilesionally and 766 (64%) intralesionally. Radiographic CR was achieved in 69% of cases. Multivariate analysis demonstrated that perilesional tumor resection was associated with a significantly higher rate of CR than intralesional resection (81% vs 62%, multivariate odds ratio = 2.5, 95% confidence interval: 1.8-3.4, P < .001). Among tumors in eloquent cortex, multivariate analysis showed that patients who underwent perilesional resection had a higher rate of CR (79% vs 58%, respectively, P < .001) and a lower rate of neurological complications (11% vs 20%, respectively, P = .018) than those who underwent intralesional resection.
CONCLUSION
Circumferential perilesional resection of GBM is associated with significantly higher rates of CR and lower rates of neurological complications than intralesional resection, even for tumors arising in eloquent locations. Perilesional resection, when feasible, should be considered as a preferred option.
Video Abstract
10.1093/neuros/nyz008
Video Abstract
Summary Video of Perilesional Resection of Glioblastoma Is Independently Associated With Improved Outcomes.
10.1093.neuros.nyz008
6005686384001
Substantial evidence suggests that a key distinction in the classification of human emotion is that between an appetitive motivational system associated with positive or pleasant emotion and an ...aversive motivational system associated with negative or unpleasant emotion. To explore the neural substrates of these two systems, 12 healthy women viewed sets of pictures previously demonstrated to elicit pleasant, unpleasant and neutral emotion, while positron emission tomographic (PET) measurements of regional cerebral blood flow were obtained. Pleasant and unpleasant emotions were each distinguished from neutral emotion conditions by significantly increased cerebral blood flow in the vicinity of the medial prefrontal cortex (Brodmann's area 9), thalamus, hypothalamus and midbrain (
P<0.005). Unpleasant was distinguished from neutral or pleasant emotion by activation of the bilateral occipito-temporal cortex and cerebellum, and left parahippocampal gyrus, hippocampus and amygdala (
P<0.005). Pleasant was also distinguished from neutral but not unpleasant emotion by activation of the head of the left caudate nucleus (
P<0.005). These findings are consistent with those from other recent PET studies of human emotion and demonstrate that there are both common and unique components of the neural networks mediating pleasant and unpleasant emotion in healthy women.
The persistence of moderate ischemic mitral regurgitation (IMR) after isolated coronary artery bypass graft surgery is an important independent predictor of long-term mortality. The aim of the ...present study was to identify predictors of postoperative improvement in moderate IMR in patients with ischemic heart disease undergoing elective isolated coronary artery bypass graft surgery.
The study population consisted of 135 patients with ischemic heart disease (age, 65+/-9 years; 81% male) and moderate IMR undergoing isolated coronary artery bypass graft surgery. Fourteen patients died before the 12-month follow-up echocardiography and were excluded. At the 12-month follow-up, 57 patients showed no or mild IMR (improvement group), whereas 64 patients failed to improve (failure group). Before coronary artery bypass graft surgery, the improvement group had significantly more viable myocardium and less dyssynchrony between papillary muscles than the failure group (P<0.001). All other preoperative parameters were similar in both groups. Large extent (> or =5 segments) of viable myocardium (odds ratio, 1.45; 95% confidence interval, 1.22 to 1.89; P<0.001) and absence (<60 ms) of dyssynchrony (odds ratio, 1.49; 95% confidence interval, 1.29 to 1.72; P<0.001) were independently associated with improvement in IMR. The majority (93%) of patients with viable myocardium and an absence of dyssynchrony showed an improvement in IMR. In contrast, only 34% and 18% of patients with dyssynchrony and nonviable myocardium, respectively, showed an improvement in IMR, whereas 32% and 49%, respectively, of these patients showed worsening of IMR (P<0.001).
Reliable improvement in moderate IMR by isolated coronary artery bypass graft surgery was observed only in patients with concomitant presence of viable myocardium and absence of dyssynchrony between papillary muscles.
Efforts to catalog global biodiversity have often focused on aboveground taxonomic diversity, with limited consideration of belowground communities. However, diversity aboveground may influence the ...diversity of belowground communities and vice versa. In addition to taxonomic diversity, the structural diversity of plant communities may be related to the diversity of soil bacterial and fungal communities, which drive important ecosystem processes but are difficult to characterize across broad spatial scales. In forests, canopy structural diversity may influence soil microorganisms through its effects on ecosystem productivity and root architecture, and via associations between canopy structure, stand age, and species richness. Given that structural diversity is one of the few types of diversity that can be readily measured remotely (e.g., using light detection and ranging—LiDAR), establishing links between structural and microbial diversity could facilitate the detection of belowground biodiversity hotspots. We investigated the potential for using remotely sensed information about forest structural diversity as a predictor of soil microbial community richness and composition. We calculated LiDAR‐derived metrics of structural diversity as well as a suite of stand and soil properties from 38 forested plots across the central hardwoods region of Indiana, USA, to test whether forest canopy structure is linked with the community richness and diversity of four key soil microbial groups: bacteria, fungi, arbuscular mycorrhizal (AM) fungi, and ectomycorrhizal (EM) fungi. We found that the density of canopy vegetation is positively associated with the taxonomic richness (alpha diversity) of EM fungi, independent of changes in plant taxonomic richness. Further, structural diversity metrics were significantly correlated with the overall community composition of bacteria, EM, and total fungal communities. However, soil properties were the strongest predictors of variation in the taxonomic richness and community composition of microbial communities in comparison with structural diversity and tree species diversity. As remote sensing tools and algorithms are rapidly advancing, these results may have important implications for the use of remote sensing of vegetation structural diversity for management and restoration practices aimed at preserving belowground biodiversity.
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