De-escalation strategies in HER2-positive early breast cancer (EBC): final analysis of the WSG-ADAPT HER2+/HR- phase II trial: efficacy, safety, and predictive markers for 12 weeks of neoadjuvant dual blockade with trastuzumab and pertuzumab ± weekly paclitaxel.

BACKGROUND: Response rates in HER2-overexpressing EBC treated with neoadjuvant chemotherapy and trastuzumab (T) have been improved by addition of pertuzumab (P). The prospective, phase II, neoadjuvant WSG-ADAPT HER2+/HR- trial assessed whether patients with strong early response to dual blockade alone might achieve pathological complete response (pCR) comparable to that of patients receiving dual blockade and chemotherapy. PATIENTS AND METHODS: Female patients with HER2+/HR- EBC (M0) were randomized (5:2) to 12 weeks of T + P ± weekly paclitaxel (pac) at 80 mg/m2. Early response was defined as proliferation decrease ≥30% of Ki-67 (versus baseline) or low cellularity (<500 invasive tumor cells) in the 3-week biopsy. The trial was designed to test non-inferiority for pCR in early responding patients of the T + P arm versus all chemotherapy-treated patients. RESULTS: From February 2014 to December 2015, 160 patients were screened, 92 were randomized to T + P and 42 to T + P+pac. Baseline characteristics were well balanced (median age 54 versus 51.5 years, cT2 51.1 versus 52.4%, cN0 54.3 versus 61.9%); 91.3% of patients completed T + P per protocol and 92.9% T + P+pac. The pCR rate in the T + P+pac arm was 90.5%, compared with 36.3% in the T + P arm as a whole. In the T + P arm, 24/92 were classified as non-responders, and their pCR rate was only 8.3% compared with 44.7% in responders (38/92) and 42.9% in patients with unclassified early response (30/92). No new safety signals were observed in the study population. CONCLUSION: Addition of taxane monotherapy to dual HER2 blockade in a 12-week neoadjuvant setting substantially increases pCR rates in HER2+/HR- EBC compared with dual blockade alone, even within early responders to dual blockade. Early non-response under dual blockade strongly predicts failure to achieve pCR.

Response of soil respiration to changes in soil temperature and water table level in drained and restored peatlands of the southeastern United States.

BACKGROUND: Extensive drainage of peatlands in the southeastern United States coastal plain for the purposes of agriculture and timber harvesting has led to large releases of soil carbon as carbon dioxide (CO2) due to enhanced peat decomposition. Growth in mechanisms that provide financial incentives for reducing emissions from land use and land-use change could increase funding for hydrological restoration that reduces peat CO2 emissions from these ecosystems. Measuring soil respiration and physical drivers across a range of site characteristics and land use histories is valuable for understanding how CO2 emissions from peat decomposition may respond to raising water table levels. We combined measurements of total soil respiration, depth to water table from soil surface, and soil temperature from drained and restored peatlands at three locations in eastern North Carolina and one location in southeastern Virginia to investigate relationships among total soil respiration and physical drivers, and to develop models relating total soil respiration to parameters that can be easily measured and monitored in the field. RESULTS: Total soil respiration increased with deeper water tables and warmer soil temperatures in both drained and hydrologically restored peatlands. Variation in soil respiration was more strongly linked to soil temperature at drained (R2 = 0.57, p < 0.0001) than restored sites (R2 = 0.28, p < 0.0001). CONCLUSIONS: The results suggest that drainage amplifies the impact of warming temperatures on peat decomposition. Proxy measurements for estimation of CO2 emissions from peat decomposition represent a considerable cost reduction compared to direct soil flux measurements for land managers contemplating the potential climate impact of restoring drained peatland sites. Research can help to increase understanding of factors influencing variation in soil respiration in addition to physical variables such as depth to water table and soil temperature.

High mangrove density enhances surface accretion, surface elevation change, and tree survival in coastal areas susceptible to sea-level rise.

Survival, growth, aboveground biomass accumulation, sediment surface elevation dynamics and nitrogen accumulation in sediments were studied in experimental treatments planted with four different densities (6.96, 3.26, 1.93 and 0.95 seedlings m(-2)) of the mangrove Rhizophora mucronata in Puttalam Lagoon, Sri Lanka. Measurements were taken over a period of 1,171 days and were compared with those from unplanted controls. Trees at the lowest density showed significantly reduced survival, whilst measures of individual tree growth did not differ among treatments. Rates of surface sediment accretion (means ± SE) were 13.0 (±1.3), 10.5 (±0.9), 8.4 (±0.3), 6.9 (±0.5) and 5.7 (±0.3) mm year(-1) at planting densities of 6.96, 3.26, 1.93, 0.95, and 0 (unplanted control) seedlings m(-2), respectively, showing highly significant differences among treatments. Mean (±SE) rates of surface elevation change were much lower than rates of accretion at 2.8 (±0.2), 1.6 (±0.1), 1.1 (±0.2), 0.6 (±0.2) and -0.3 (±0.1) mm year(-1) for 6.96, 3.26, 1.93, 0.95, and 0 seedlings m(-2), respectively. All planted treatments accumulated greater nitrogen concentrations in the sediment compared to the unplanted control. Sediment %N was significantly different among densities which suggests one potential causal mechanism for the facilitatory effects observed: high densities of plants potentially contribute to the accretion of greater amounts of nutrient rich sediment. While this potential process needs further research, this study demonstrated how higher densities of mangroves enhance rates of sediment accretion and surface elevation processes that may be crucial in mangrove ecosystem adaptation to sea-level rise. There was no evidence that increasing plant density evoked a trade-off with growth and survival of the planted trees. Rather, facilitatory effects enhanced survival at high densities, suggesting that managers may be able to take advantage of high plantation densities to help mitigate sea-level rise effects by encouraging positive sediment surface elevation.

Management of late recurrence of a low-grade endometrial stromal sarcoma (LGESS): treatment with letrozole.

Low grade endometrial stromal sarcoma (LGESS) is a rare disease. LGESS usually expresses steroidal receptors and is regarded to be hormone-sensitive. Due to the rarity of the tumor, only few case series have been published so far. Here, we report the case of a 36-year-old woman who underwent an abdominal hysterectomy with bilateral salpingo-oophorectomy and adjuvant radiotherapy for a G1 LGESS in 1991. Twelve years later she presented to us with pelvic and peritoneal masses. The patient was treated with letrozole achieving a partial response which is lasting 39 months. Treatment is ongoing. Aromatase inhibitors represent an interesting treatment option for LGESS.

Integration of genome-wide association and extant brain expression QTL identifies candidate genes influencing prepulse inhibition in inbred F1 mice.

Genetic association mapping in structured populations of model organisms can offer a fruitful complement to human genetic studies by generating new biological hypotheses about complex traits. Here we investigated prepulse inhibition (PPI), a measure of sensorimotor gating that is disrupted in a number of psychiatric disorders. To identify genes that influence PPI, we constructed a panel of half-sibs by crossing 30 females from common inbred mouse strains with inbred C57BL/6J males to create male and female F1 offspring. We used publicly available single nucleotide polymorphism (SNP) genotype data from these inbred strains to perform a genome-wide association scan using a dense panel of over 150,000 SNPs in a combined sample of 604 mice representing 30 distinct F1 genotypes. We identified two independent PPI-associated loci on Chromosomes 2 and 7, each of which explained 12-14% of the variance in PPI. Searches of available databases did not identify any plausible causative coding polymorphisms within these loci. However, previously collected expression quantitative trait locus (eQTL) data from hippocampus and striatum indicated that the SNPs on Chromosomes 2 and 7 that showed the strongest association with PPI were also strongly associated with expression of several transcripts, some of which have been implicated in human psychiatric disorders. This integrative approach successfully identified a focused set of genes which can be prioritized for follow-up studies. More broadly, our results show that F1 crosses among common inbred strains can be used in combination with other informatics and expression datasets to identify candidate genes for complex behavioral traits.

Gemcitabine, epirubicin and docetaxel as primary systemic therapy in patients with early breast cancer: results of a multicentre phase I/II study.

Developing primary systemic chemotherapy (PST) regimens that induce higher pathological complete response (pCR) rates remains a challenge in operable breast cancer. We recruited 77 eligible patients into a multicentre phase I/II study to evaluate the maximum tolerated dose (MTD), toxicity and efficacy of preoperative gemcitabine day 1 and 8 (800 mg/m(2) fixed dose), epirubicin and docetaxel on day 1 (doses escalated from 60 mg/m(2)) (GEDoc), repeated 3-weekly for 6 cycles with filgrastim support. MTD for epirubicin was 90 mg/m(2) and for docetaxel 75 mg/m(2). Dose-limiting toxicities (DLTs) included febrile neutropenia and grade 3 diarrhoea. Clinical response rate was 92%, pCR rate was 26%. 79% of patients had breast-conserving surgery. Grade 3/4 leucopenia was the main toxicity, occurring in 55 (87%) of 63 patients treated at the MTD. Non-haematological toxicity caused no serious clinical problems. In conclusion, GEDoc is highly active as PST. Efficacy and toxicity compare favourably with other effective combinations.

Angina following myocardial revascularization. Does time of recurrence predict etiology and influence results of operation?

To assess the operative mortality and long-term results in patients undergoing repeat revascularization for recurrent angina, we analyzed 48 consecutive patients operated upon at New York University Medical Center between 1970 and 1978. Between January, 1970, and July, 1973, 15 patients underwent repeat revascularization with five operative deaths (33 percent). Thirty-three patients underwent similar operations from July, 1973, to July, 1978, with only one operative death (3 percent). Technical factors and improved methods of myocardial protection during the operation directly influence this decrease in operative mortality rate. The indication for reoperation was incapacitating angina developing within 2 months of the inital operation in 18 patients (early failures) and after more than 2 months in 30 patients (late failures). The early failures were most commonly attributed to technical factors (33 percent) and graft occlusion by exuberant pericardial scarring (33 percent). The late failures were commonly related to the development of new native coronary lesions (47 percent) and selection of an incorrect site for distal anastomoses (23 percent). The prognostic and therapeutic implications of these findings will be discussed in detail. Angina was abolished or significantly decreased in 90 percent of the survivors, and there were only two late deaths occuring 18 and 20 months postoperatively. These data indicate that patients undergoing repeat myocardial revascularization can be operated upon with low operative mortality rates and symptomatic improvement comparable to that of patients undergoing coronary artery bypass for the first time.

Transport and in vivo elimination of cysteinyl leukotrienes.

Transport processes control not only synthesis and release of LTC4 but also the elimination and excretion of LTC4 and its metabolites. (i) A primary-active ATP-dependent export carrier mediates the release of LTC4 from a leukotriene-generating cell, as exemplified by mastocytoma cells, and as measured in mastocytoma plasma membrane vesicles (2). (ii) Release of cysteinyl leukotrienes into the blood circulation is followed by a rapid elimination with an initial half-life of 38 sec in rats and 4.0 min in man, as measured with the labeled, representative LTC4 catabolite, N-acetyl-LTE4. (iii) 11C-labeled N-acetyl-LTE4 can serve for non-invasive studies on cysteinyl leukotriene elimination and excretion by the liver and kidney in the intact organism using positron emission tomography. An impairment of leukotriene transport from the liver across the canalicular membrane into bile, studied in mutant rats and in extrahepatic cholestasis, leads to a compensatory diversion of cysteinyl leukotriene elimination to the kidney. N-Acetyl-LTE4 labeled with a short-lived positron-emitting isotope provides quantitative insight into the pathways of cysteinyl leukotriene elimination in vivo. (iv) Cysteinyl leukotriene export from the liver into bile is mediated by an ATP-dependent primary-active export carrier. This decisive step in cysteinyl leukotriene elimination has been characterized in hepatocyte canalicular membrane vesicles (3). The leukotriene exporter is deficient in transport mutant rats. The leukotriene carrier is distinct from other ATP-dependent export carriers identified in this membrane domain, such as the ATP-dependent bile salt export carrier (25) and the multidrug export carrier (27).

Selective breeding for negative contrast in consummatory behavior.

Rats showing either large or small reductions in licking following a shift from 32% to 4% sucrose were selectively bred for 7 generations. Rats from the 2 resulting lines reliably differed in successive negative contrast and in activity (radial-arm maze and open field). Differences in activity and contrast were not correlated. Heritability (h2) of the reaction to sucrose shift was reliable in the last 6 filial generations and equaled 0.64 in the F7 generation. The 2 lines did not differ (a) in response to the absolute rewarding value of sucrose or cocaine; (b) in open-field defecations or thigmotaxis; (c) in anticipatory contrast; or (d) in responsivity to midazolam. Responsivity to reward reduction may involve a relatively delimited psychological process that is amenable to selection.

Rejecting conventional wisdom: how academic medical centers can regain their leadership positions.

Academic medical centers (i.e., medical schools and their principal hospitals) are following very similar strategies in attempts to secure their futures. It is likely that these undifferentiated strategies will fail, since most of them have been copied from the lower-cost, geographically better-positioned hospitals and health systems. Despite a wealth of innovative, entrepreneurial talent and the potential to reshape the world that AMCs live in, most AMCs are in reactive modes. Future directions and strategies are almost always shaped, forced, and justified by external pressures. The major problem with the strategic plans of most AMCs is that they are based on conventional industry wisdom. Strategic plans tend not to be analytically driven. The insight and understanding of those factors that drive the demand for AMCs' services and determine the performances of AMCs are lacking. The authors note some questions that are critical to the formulation of strategies for AMCs. For example, how can the research mission be changed from a cost-based to a value-based endeavor? Most AMCs cannot answer these questions, and if they do address them in the planning process, they do so superficially. Several examples of the factors that need to be understood are also given, such as patients' purposes and needs in seeking specialty care. Alternative strategies are listed, such as maintaining and exploiting the economic irrationality of the market rather than acting as if it were economically rational or forcing it to become so. Last, the authors outline the scope of the changes that are required and urge AMCs to reject conventional wisdom, determine their own unique situations, and work from there.

Relative hedonic value modulates anticipatory contrast.

Intake of an initial substance (e.g., 0.15% saccharin) is suppressed when the presentation of this substance precedes the availability of a preferred solution (e.g., 32% sucrose) in brief daily pairings. The present experiments show that degree of this anticipatory contrast effect is related to the relative hedonic value of the substances paired each day. When the initial substance has low hedonic value relative to the second substance (e.g., water or empty tube paired with 32% sucrose), then a facilitation effect rather than contrast occurs. As the hedonic value of the initial substance increases (0.0015% saccharin, 0.5% sucrose, 0.015% saccharin, 1% sucrose, 2% sucrose, 0.15% saccharin), facilitation is replaced by contrast, which develops sooner and becomes larger the greater the hedonic value of the initial substance. The serotonin antagonist cyproheptadine increased absolute lick frequencies, but did not alter contrast. The serotonin1A agonist buspirone tended to decrease absolute lick frequencies, but did not alter contrast. The occurrence of contrast is discussed in terms of response competition, inhibition, and devaluation of the initial substance.

Effect of serotonergic drugs on negative contrast in consummatory behavior.

The effect of acute and chronic administration of the 5-HT1A agonist buspirone on successive negative contrast was investigated in Experiments 1-6. Contrast in consummatory behavior was induced by shifting rats from a 32% to a 4% sucrose solution. Experiments 1-5 showed that buspirone (0.125, 0.25, 0.5, 1.0, 2.0, 15.0 mg/kg) was ineffective in alleviating contrast or in facilitating recovery from contrast. The 15 mg/kg dose substantially decreased consummatory responding. Experiment 6 showed that the chronic (24 days) administration of buspirone (0.5, 2.0 mg/kg) also did not alleviate contrast. The chronic, but not the acute administration of the 2.0 mg/kg dose decreased consummatory behavior. In Experiment 7 the 5-HT1A agonist gepirone (2.5, 5.0 and 10.0 mg/kg) was also found to be ineffective in reducing contrast but, at the higher doses, decreased overall sucrose intake. Experiments 8 and 9 found that the 5-HT2 antagonists ketanserin (2.0 and 8.0 mg/kg) and ritanserin (0.63 and 2.5 mg/kg) also did not alleviate contrast. Midazolam (1.0 mg/kg), included as a positive control, eliminated contrast. These data suggest that serotonergic mechanisms are not involved in negative contrast.

Photosynthetic light response of flooded cherrybark oak (Quercus pagoda) seedlings grown in two light regimes.

Two-year-old cherrybark oak (Quercus pagoda Raf.) seedlings raised in full or partial (27%) sunlight were flooded for 30 days to study the effects of light availability and root inundation on photosynthetic light response. Compared with seedlings receiving full sunlight, seedlings receiving partial sunlight developed leaves with 90% greater blade area, 26% less mass per unit volume, and 35% lower nitrogen (N) concentration per unit area, leading to a 15% reduction in leaf photosynthetic capacity when carbon exchange rates were based on blade area. However, when carbon exchange rates were based on leaf mass, leaves acclimated to partial sunlight exhibited a 15% greater photosynthetic capacity realized primarily through an increased initial slope of the photosynthetic light response (A/PPFD) curve and increased net photosynthesis at leaf saturation (Amax). Short-term flooding increased leaf mass per unit area more than 19%, reduced foliar N concentrations per unit dry mass by 19%, and initiated reductions in Amax and apparent quantum yield (phi) of seedlings in both light regimes. Greatest impairment of Amax (56% area basis, 65% mass basis) and phi (40%) were observed in leaves receiving full sunlight, and the declines were concomitant with a 35% decrease in chlorophyll concentration. Flooding also depressed instantaneous photosynthetic N-use efficiency (PPNUE) such that Amax decreased 54%, and the initial slope of PPNUE/PPFD curves decreased 33 and 50% for leaves acclimated to partial and full sunlight, respectively. The A/PPFD patterns indicated that the magnitude of flood-induced inhibition of the photosynthetic mechanism of cherrybark oak seedlings is determined partly by the light environment.

The effects of deep pressure touch on anxiety.

Occupational therapists who work with hyperactive children and adults who are in an aroused state sometimes employ deep pressure touch (DPT) as a therapeutic method to achieve calmer behavior. This pilot study attempts to measure effects of DPT on objective and subjective anxiety. Twenty-three healthy college students, serving as their own controls, self-administered DPT via a specially designed apparatus. Heart rate and self-reported anxiety were compared under conditions of DPT (experimental) and confinement without DPT (control). Data on subjects' trait anxiety also were analyzed. Although the group as a whole did not relax significantly more under experimental conditions than under control conditions, the degree of subjective relaxation was greater in the experimental group. These results, coupled with a significant intragroup difference in the response of subjects with high trait anxiety, were encouraging. This study provides direction and focus to investigators interested in further research on the validation of an empirically useful treatment technique.

[MR imaging of the breast before and after neoadjuvant treatment - enhancement characteristics and T 2 signal intensity of breast cancers and breast parenchyma]. / MR-Mammografie vor und nach neoadjuvanter Systemtherapie - Enhancementcharakteristika und T 2-Signalinintensität von Mammakarzinomen und Drüsenparenchym.

PURPOSE: Analysis of enhancement characteristics and T 2 signal intensity (SI) of breast cancers and normal breast parenchyma on MR imaging (MRI) before and after neoadjuvant treatment (NT) to improve the assessment of therapy response. MATERIALS AND METHODS: Retrospective data analysis of 43 consecutive patients (mean age 49.9 years) with invasive breast cancers (T2 /T3) who received NT. Evaluation of breast MRI before and after NT with assessment of therapy response according to RECIST criteria as well as calculation of the maximum initial enhancement (Enh (max)), delayed enhancement (Enh (post)) and T 2 SI by ROI analyses of breast cancers and breast parenchyma. Comparison of therapy response and enhancement characteristics. RESULTS: Therapy response on MRI: 16.3 % (n = 7) complete remission (CR (MRT)), 53.5 % (n = 23) partial remission (PR (MRT)), 27.9 % (n = 12) stable disease (SD (MRT)) und 2.3 % (n = 1) progressive disease (PD (MRT)). Breast cancers showed a significant decrease in Enh (max) and T 2 SI as well as a significant increase in Enh (post) after NT (p < 0.01). Not any SI parameter of normal breast parenchyma showed a significant change after NT (p > 0.05). All cases with CR (MRT) had wash out or plateau shape of the SI time curve before NT and showed continuous enhancement thereafter. CONCLUSION: Breast MRI shows significant changes in enhancement characteristics and T 2 SI of breast cancers after NT, whereas normal breast parenchyma remains unchanged. SI data could possibly help to improve the assessment of therapy response by MRI. Prospective trials with larger study cohorts and MRI monitoring during NT are necessary to validate these results.

The myth of group buying leverage.

To deal with current cost pressures, most hospitals have focused on reducing costs by negotiating lower prices for supply items. But such strategies are not as successful as hospitals believe, say an analyst at Booz, Allen & Hamilton. In fact, manufacturer pricing to hospitals is more market-driven than volume-driven, he argues, and group buying leverage is largely illusory. To truly reduce costs, hospitals need to find more effective ways of managing their supply costs.