Tucatinib versus placebo added to trastuzumab and capecitabine for patients with pretreated HER2+ metastatic breast cancer with and without brain metastases (HER2CLIMB): final overall survival analysis.

BACKGROUND: In the primary analysis of the HER2CLIMB trial, tucatinib added to trastuzumab and capecitabine significantly improved overall survival (OS) and progression-free survival (PFS) in patients with human epidermal growth factor receptor 2 positive (HER2+) metastatic breast cancer. We report efficacy and safety outcomes, including the final OS and safety outcomes from follow-up in HER2CLIMB. PATIENTS AND METHODS: HER2CLIMB is a randomized, double-blind, placebo-controlled trial in patients with locally advanced or metastatic HER2+ breast cancer, including patients with brain metastases. Patients were randomized 2 : 1 to receive tucatinib or placebo, in combination with trastuzumab and capecitabine. After the primary analysis (median follow-up of 14 months), the protocol was amended to allow for unblinding sites to treatment assignment and cross-over from the placebo combination to the tucatinib combination. Protocol prespecified descriptive analyses of OS, PFS (by investigator assessment), and safety were carried out at ∼2 years from the last patient randomized. RESULTS: Six hundred and twelve patients enrolled in the HER2CLIMB trial. At a median OS follow-up of 29.6 months, median duration of OS was 24.7 months for the tucatinib combination group versus 19.2 months for the placebo combination group [hazard ratio (HR) for death: 0.73, 95% confidence interval (CI): 0.59-0.90, P = 0.004] and OS at 2 years was 51% and 40%, respectively. HRs for OS across prespecified subgroups were consistent with the HR for the overall study population. Median duration of PFS was 7.6 months for the tucatinib combination group versus 4.9 months for the placebo combination group (HR for progression or death: 0.57, 95% CI: 0.47-0.70, P < 0.00001) and PFS at 1 year was 29% and 14%, respectively. The tucatinib combination was well tolerated with a low rate of discontinuation due to adverse events. CONCLUSIONS: With additional follow-up, the tucatinib combination provided a clinically meaningful survival benefit for patients with HER2+ metastatic breast cancer.

Early and late studies of EMD use in periodontal intrabony defects.

BACKGROUND AND OBJECTIVE: The clinical efficacy of EMDs for the treatment of periodontal infrabony defects has been reported. However, recent publications have questioned the validity of results from early findings. Hence, the purpose of this study was to compare the results obtained from early and late studies when EMD was used as an adjunct in treating human intrabony defects during flap surgery. The aim of this meta-analysis was to evaluate the validity of results published from early studies compared with those published from later studies. MATERIAL AND METHODS: PubMed and MEDLINE searches were performed. The evaluation period was 1997-2010 and it was divided into two groups of equal periods of time: early studies (1997-2003) and late studies (2004-2010). The clinical parameters assessed were clinical attachment level (CAL), probing pocket depth and bone gain (BG; measured as a percentage or in mm). RESULTS: No statistically significant difference was found between the results obtained from early studies (1997-2003) and late studies (2004-2010) with regards to CAL gain, probing pocket depth reduction and BG. Nonetheless, both study periods showed a benefit for using EMD to treat periodontal infrabony defects when compared with the groups without EMD during open flap surgery. CONCLUSIONS: The results obtained from this study failed to show any potential differences between the results published from early studies and late studies with regards to the clinical effectiveness of EMD in treating periodontal infrabony defects.

Mobility, mortality, and the middle ages: identification of migrant individuals in a 14th century black death cemetery population.

Mobility and migration patterns of groups and individuals have long been a topic of interest to archaeologists, used for broad explanatory models of cultural change as well as illustrations of historical particularism. The 14th century AD was a tumultuous period of history in Britain, with severely erratic weather patterns, the Great Famine of 1315-1322, the Scottish Wars of Independence, and the Hundred Years' War providing additional migration pressures to the ordinary economic issues drawing individuals to their capital under more stable conditions. East Smithfield Black Death Cemetery (Royal Mint) had a documented use period of only 2 years (AD 1348-1350), providing a precise historical context (∼50 years) for data. Adults (n = 30) from the East Smithfield site were sampled for strontium and oxygen stable isotope analyses of tooth enamel. Five individuals were demonstrated to be statistical outliers through the combined strontium and oxygen isotope data. Potential origins for migrants ranged from London's surrounding hinterlands to distant portions of northern and western Britain. Historic food sourcing practices for London were found to be an important factor for consideration in a broader than expected (87) Sr/(86) Sr range reflected in a comparison of enamel samples from three London datasets. The pooled dataset demonstrated a high level of consistency between site data, divergent from the geologically predicted range. We argue that this supports the premise that isotope data in human populations must be approached as a complex interaction between behavior and environment and thus should be interpreted cautiously with the aid of alternate lines of evidence.

Assessment of the management of carcinomatous meningitis from breast cancer globally: a study by the Breast International Group Brain Metastasis Task Force.

BACKGROUND: Carcinomatous meningitis (CM) is a severe complication of breast cancer. The Breast International Group (BIG) carried out a survey to describe the approach to CM internationally. PATIENTS AND METHODS: A questionnaire on the management of CM was developed by the Brain Metastases Task Force of BIG and distributed to its groups, requesting one answer per group site. RESULTS: A total of 241 sites responded, 119 from Europe, 9 from North America, 39 from Central/South America, 58 from Asia, and 16 in Australia/New Zealand, with 24.5% being general hospitals with oncology units, 44.4% university hospitals, 22.4% oncology centers, and 8.7% private hospitals. About 56.0% of sites reported seeing <5 cases annually with 60.6% reporting no increase in the number of cases of CM recently. Nearly 63.1% of sites investigate for CM when a patient has symptoms or radiological evidence, while 33.2% investigate only for symptoms. For diagnosis, 71.8% of sites required a positive cerebrospinal fluid cytology, while magnetic resonance imaging findings were sufficient in 23.7% of sites. Roughly 97.1% of sites treat CM and 51.9% also refer patients to palliative care. Intrathecal therapy is used in 41.9% of sites, mainly with methotrexate (74.3%). As many as 20 centers have a national registry for patients with breast cancer with central nervous system metastases and of those 5 have one for CM. Most (90.9%) centers would be interested in participating in a registry as well as in studies for CM, the latter preferably (62.1%) breast cancer subtype specific. CONCLUSIONS: This is the first study to map out the approach to CM from breast cancer globally. Although guidelines with level 1 evidence are lacking, there is a high degree of homogeneity in the approach to CM globally and great interest for conducting studies in this area.

STED nanoscopy reveals molecular details of cholesterol- and cytoskeleton-modulated lipid interactions in living cells.

Details about molecular membrane dynamics in living cells, such as lipid-protein interactions, are often hidden from the observer because of the limited spatial resolution of conventional far-field optical microscopy. The superior spatial resolution of stimulated emission depletion (STED) nanoscopy can provide new insights into this process. The application of fluorescence correlation spectroscopy (FCS) in focal spots continuously tuned down to 30 nm in diameter distinguishes between free and anomalous molecular diffusion due to, for example, transient binding of lipids to other membrane constituents, such as lipids and proteins. We compared STED-FCS data recorded on various fluorescent lipid analogs in the plasma membrane of living mammalian cells. Our results demonstrate details about the observed transient formation of molecular complexes. The diffusion characteristics of phosphoglycerolipids without hydroxyl-containing headgroups revealed weak interactions. The strongest interactions were observed with sphingolipid analogs, which showed cholesterol-assisted and cytoskeleton-dependent binding. The hydroxyl-containing headgroup of gangliosides, galactosylceramide, and phosphoinositol assisted binding, but in a much less cholesterol- and cytoskeleton-dependent manner. The observed anomalous diffusion indicates lipid-specific transient hydrogen bonding to other membrane molecules, such as proteins, and points to a distinct connectivity of the various lipids to other membrane constituents. This strong interaction is different from that responsible for forming cholesterol-dependent, liquid-ordered domains in model membranes.

Migration towards Bangladesh coastlines projected to increase with sea-level rise through 2100.

To date, projections of human migration induced by sea-level change (SLC) largely suggest large-scale displacement away from vulnerable coastlines. However, results from our model of Bangladesh suggest counterintuitively that people will continue to migrate toward the vulnerable coastline irrespective of the flooding amplified by future SLC under all emissions scenarios until the end of this century. We developed an empirically calibrated agent-based model of household migration decision-making that captures the multi-faceted push, pull and mooring influences on migration at a household scale. We then exposed ~4800 000 simulated migrants to 871 scenarios of projected 21st-century coastal flooding under future emissions pathways. Our model does not predict flooding impacts great enough to drive populations away from coastlines in any of the scenarios. One reason is that while flooding does accelerate a transition from agricultural to non-agricultural income opportunities, livelihood alternatives are most abundant in coastal cities. At the same time, some coastal populations are unable to migrate, as flood losses accumulate and reduce the set of livelihood alternatives (so-called 'trapped' populations). However, even when we increased access to credit, a commonly-proposed policy lever for incentivizing migration in the face of climate risk, we found that the number of immobile agents actually rose. These findings imply that instead of a straightforward relationship between displacement and migration, projections need to consider the multiple constraints on, and preferences for, mobility. Our model demonstrates that decision-makers seeking to affect migration outcomes around SLC would do well to consider individual-level adaptive behaviors and motivations that evolve through time, as well as the potential for unintended behavioral responses.

Tumor cell dormancy: implications for the biology and treatment of breast cancer.

Despite progress made in the therapy of solid tumors such as breast cancer, the prognosis of patients even with small primary tumors is still limited by metastatic relapse often long after removal of the primary tumor. Therefore, it has been hypothesized that primary tumors shed tumor cells already at an early stage into the blood circulation. A subset of these disseminated tumor cells may persist in a state of so-called "dormancy". Based on cell culture and animal models, dormancy can occur at two different stages. Single dormant cells are defined as cells with a lack of proliferation and apoptosis with the cells undergoing cell cycle arrest. The micrometastasis model defines tumor cell dormancy as a state of balanced apoptosis and proliferation of micrometastasis resulting in no net increase of tumor mass. Mechanisms leading to a growth activation of dormant tumor cells and the outgrowth of manifest metastases are not completely understood. Genetic predisposition of the dormant cells as well as immunological and angiogenetic influences of the surrounding environment may contribute to this phenomenon. In this review, we summarize findings on different factors for tumor cell dormancy and potential therapeutic implications that should help to reduce metastatic relapse in cancer patients.

Dependence on smoking and the acoustic startle response in healthy smokers.

Recent data from nicotine-dependent rats (14) and healthy smokers (18) would suggest that nicotine withdrawal modulates the acoustic startle reflex in a way similar to that of fear (5,20). We examined this directly using nonsmokers and healthy smokers who had no deprivation, brief deprivation (2-3 h), or prolonged deprivation (15 h). Groups differences in heart rate (HR), alveolar carbon monoxide (CO) levels, and desire and craving for cigarettes confirmed the presence of smoking withdrawal. However, there were no significant differences in the magnitude of the baseline startle response among the differently deprived smokers or between the smokers and the nonsmokers. Subsequent startle tests were carried out in the smokers during repeated sequences of preparing a cigarette for smoking (smoking cues) and then smoking. Whereas we did find statistically significant interactions of smoking deprivation with smoking cues and with renewed smoking, there was only weak confirmation of a priori predictions of motivational effects of smoking cues or of smoking. We conclude that smoking dependence may not affect the acoustic startle response itself; modulation seems to occur, but only after experience with the test situation. Discussed were possible mechanisms of this modulation in both humans and animals and further application of the startle response for providing interdisciplinary assessments of the motivational effects of nicotine withdrawal.

Prediction of height velocity of prepubertal children with growth hormone deficiency in the first year of treatment with recombinant human growth hormone.

AIM: Several methods have been developed to predict the outcome of growth hormone (GH) therapy in children with growth hormone deficiency (GHD). METHODS: Over 50 factors for each of 92 prepubertal patients with GHD (26 patients with total and 45 patients with partial GHD, 21 patients with neurosecretory dysfunction) were collected and included in multiple regression analyses and other nonlinear models to predict height velocity (HV) (cm/yr) in the first year of treatment. Afterwards the model was validated by two other cohorts of patients from other universities, which followed the same treatment regime as our clinic. RESULTS: Twelve parameters had a significant correlation to HV (p<0.05) and a coefficient of determination >20%. Two parameters (In BA, In GHmax) showed a coefficient of determination >60% for children with GHD in multiple regression analysis. The validation of the mathematical model against another data set showed different results. GH was measured by the same method, but BA was scored at the first clinic as in our clinic by only one doctor and in the other university by several radiologists. The accuracy of prediction in the first clinic was significantly higher than in the other university. CONCLUSION: This model demonstrates that exact scoring of BA and precise measurement of GHmax in the stimulation test is necessary, and if carried out carefully leads to useful prediction values for determining height velocity.

[Expression of hepatitis A virus procapsids in the insect cells infected by recombinant baculovirus]. / Ekspressia prokapsidov virusa gepatita A v infitsirovannykh rekombinantnym bakulovirusom kletkakh nasekomykh.

The recombinant baculocvirus containing genome P1-2A-P3 of hepatitis A virus (HAV) was constructed and used for infecting the Sf9 insect cells. It was demonstrated that the deletion of 2BC from HAV polyprotein and the insertion of a new 3C protease cleavage site between P1-2A and P3 did not interfere with the processing of polyprotein or with forming the 70S-procapsids. The identity of the protein contents as well as of morphological and antigen characteristics, obtained in Sf9-cells, to HAV empty capsids, which take shape in the infected mammal cells, proves that it is possible to use them in making the vaccine and diagnostic preparations.

Heat Stress Increases Long-term Human Migration in Rural Pakistan.

Human migration attributable to climate events has recently received significant attention from the academic and policy communities (1-2). Quantitative evidence on the relationship between individual, permanent migration and natural disasters is limited (3-9). A 21-year longitudinal survey conducted in rural Pakistan (1991-2012) provides a unique opportunity to understand the relationship between weather and long-term migration. We link individual-level information from this survey to satellite-derived measures of climate variability and control for potential confounders using a multivariate approach. We find that flooding-a climate shock associated with large relief efforts-has modest to insignificant impacts on migration. Heat stress, however-which has attracted relatively little relief-consistently increases the long-term migration of men, driven by a negative effect on farm and non-farm income. Addressing weather-related displacement will require policies that both enhance resilience to climate shocks and lower barriers to welfare-enhancing population movements.

Perioperative morbidity and outcome of secondary cytoreduction for recurrent epithelial ovarian cancer.

BACKGROUND: Despite radical surgical and chemotherapeutic treatment of ovarian cancer, the majority of patients develop recurrent disease. Secondary cytoreductive surgery can result in favourable outcome in selected patients, but information regarding feasibility, safety and perioperative outcome of these often complex procedures is limited. METHODS: Surgical parameters in patients with recurrent epithelial ovarian cancer selected for secondary cytoreduction were analysed and compared to patients undergoing primary cytoreduction. RESULTS: In total, 222 patients undergoing radical cytoreduction were analysed (48 patients for relapsed disease and 174 patients at primary diagnosis of advanced ovarian cancer). The range of surgical procedures was similar in both groups. In 48% of secondary cytoreductions 'optimal surgical results' (residual tumour <1 cm) were obtained and 33% of the patients had no residual disease compared to 82% and 58% at primary cytoreduction. There was no significant difference in perioperative complication rates. The duration of surgery was shorter and the number of transfused blood products was smaller at secondary cytoreduction (p < 0.001 and p = 0.001). CONCLUSION: Secondary cytoreduction in relapsed ovarian cancer is safe and feasible and perioperative outcome is not inferior compared to primary cytoreduction. Surgery-associated morbidity should represent a minor aspect in the selection and counselling of patients regarding treatment options for recurrent ovarian cancer.

The influence of risk estimates obtained from maternal serum screening on amniocentesis rates.

OBJECTIVE: To investigate the influence of Down syndrome risk estimates obtained from maternal serum screening (MSS) on women's choices regarding amniocentesis. METHODS: Women who screened positive for Down syndrome by an Ontario MSS program between 1993 and 1998 were grouped on the basis of their risk estimate and ethnicity. Amniocentesis uptake rates between the groups were compared in order to determine how the MSS risk estimate influenced uptake. RESULTS: Analysis of 16 792 women showed that amniocentesis uptake rates increased as the estimated risk increased. Uptake in women < or = 35 was higher than that for older women (70% vs 60%, p = 0.001). Uptake in Caucasian and Asian women was higher than the uptake in Black women (67% vs 49%, p = 0.001). Women aged 35 years or older were more likely to proceed with amniocentesis if the MSS risk estimate was higher than their age-specific risk. CONCLUSION: The increase in amniocentesis rate paralleled the increase in MSS risk estimate for Down syndrome. Risk-specific amniocentesis rates are higher in women aged less than 35 years. Women aged 35 years or older whose risk estimate by MSS is lower than their age-specific risk are less likely to opt for amniocentesis.

The effect of fetal gender on the false-positive rate of Down syndrome by maternal serum screening.

OBJECTIVES: (1) To further explore if there is a difference in maternal serum levels of alpha-fetoprotein (AFP), human chorionic gonadotrophin (hCG) and estriol (uE3) between fetal genders. (2) To determine if these differences influence false-positive rates of Down syndrome screening in pregnancies with male or female fetuses. METHODS: This is a descriptive study of women screened at the Ontario Maternal Serum Screening program between 1993 and 1995. The women were grouped by fetal gender and ethnicity. Serum levels of the three markers and screening false-positive rates for Down syndrome were compared between fetal genders in women of different ethnicity respectively. RESULTS: Complete data were available for 110 306 pregnancies. In all three ethnic groups, MSAFP levels were significantly decreased and MShCG levels were significantly increased in women with female fetuses. The level of MSuE3 was similar between genders. The difference in false-positive rates of Down syndrome between genders was not statistically significant. CONCLUSIONS: This is the largest study comparing false-positive rates between fetal genders. In contrast to previous studies, the differences in the serum marker levels between fetal genders do not influence the false-positive rates for Down syndrome.

A shared community-based practice: an alternative model for WOC nursing practice.

In the past, as the populations in many communities have grown, WOC nurses have been hired for each of the major health care facilities located in that community. However health care restructuring has caused many local hospitals to reevaluate their use of specialty practice nurses, including ET/WOC specialists. In response to this trend, a shared community practice model was established that has allowed each agency to make use of ET nursing service on an "as needed" basis, while maintaining daily accessibility to this important resource person. This article describes the evolution and growth of this practice model during the past two decades of intense reform in health care delivery.

Gluconeogenesis in developing rat kidney cortex.

1. Gluconeogenesis in developing rat kidney cortex was studied by assaying the activities of two enzymes, glucose 6-phosphatase and phosphoenolpyruvate carboxykinase, and by measuring glucose formation in tissue slices. 2. Glucose 6-phosphatase and phosphoenolpyruvate carboxykinase are present in late foetal (21-22-day-old) tissue and increase rapidly postnatally. Maximum activity of phosphoenolpyruvate carboxykinase occurs at 7 days of age, followed by a decline to the adult level. Glucose 6-phosphatase activity rises during the first 2 postnatal weeks and then declines. 3. Late foetuses synthesize glucose from both pyruvate and l-glutamate. The rate increases during the first 2 weeks to above adult levels. Synthesis is always higher from pyruvate than from glutamate. 4. The effect of 24hr. starvation was studied in perinatal animals. The results indicate that the ability to increase the rate of glucose synthesis as a result of starvation is not present at birth, but develops some time after the second postnatal day.