Combination of bevacizumab and 2-weekly pegylated liposomal doxorubicin as first-line therapy for locally recurrent or metastatic breast cancer. A multicenter, single-arm phase II trial (SAKK 24/06)

Background: Pegylated liposomal doxorubicin (PLD) and bevacizumab are active agents in the treatment of metastatic breast cancer (MBC). We carried out a multicenter, single-arm phase II trial to evaluate the toxicity and efficacy of PLD and bevacizumab as first-line treatment in MBC patients. Methods: Bevacizumab (10 mg/kg) and PLD (20 mg/m2) were infused on days 1 and 15 of a 4-week cycle for a maximum of six cycles. Thereafter, bevacizumab monotherapy was continued at the same dose until progression or toxicity. The primary objective was safety and tolerability, and the secondary objective was to evaluate efficacy of the combination. Results: Thirty-nine of 43 patients were assessable for the primary end point. Eighteen of 39 patients (46%, 95% confidence interval 30% to 63%) had a grade 3 toxicity. Sixteen (41%) had grade 3 palmar-plantar erythrodysesthesia, one had grade 3 mucositis, and one severe cardiotoxicity. Secondary end point of overall response rate among 43 assessable patients was 21%. Conclusions: In this nonrandomized single-arm trial, the combination of bimonthly PLD and bevacizumab in locally recurrent and MBC patients demonstrated higher than anticipated toxicity while exhibiting only modest activity. Based on these results, we would not consider this combination for further investigation in this settin

Bevacizumab continuation versus no continuation after first-line chemotherapy plus bevacizumab in patients with metastatic colorectal cancer: a randomized phase III non-inferiority trial (SAKK 41/06)

In this trial, stopping bevacizumab after completion of induction chemotherapy was associated with a shorter time to progression, but no statistically significant difference in overall survival compared with the bevacizumab continuation strategy. Non-inferiority could not be demonstrated. Treatment costs are substantially higher for continuous bevacizumab treatmen

Neoadjuvant chemoradiotherapy with or without panitumumab in patients with wild-type KRAS, locally advanced rectal cancer (LARC): a randomized, multicenter, phase II trial SAKK 41/07

Background We conducted a randomized, phase II, multicenter study to evaluate the anti-epidermal growth factor receptor (EGFR) mAb panitumumab (P) in combination with chemoradiotherapy (CRT) with standard-dose capecitabine as neoadjuvant treatment for wild-type KRAS locally advanced rectal cancer (LARC). Patients and methods Patients with wild-type KRAS, T3-4 and/or N+ LARC were randomly assigned to receive CRT with or without P (6 mg/kg). The primary end-point was pathological near-complete or complete tumor response (pNC/CR), defined as grade 3 (pNCR) or 4 (pCR) histological regression by Dworak classification (DC). Results Forty of 68 patients were randomly assigned to P + CRT and 28 to CRT. pNC/CR was achieved in 21 patients (53%) treated with P + CRT [95% confidence interval (CI) 36%-69%] versus 9 patients (32%) treated with CRT alone (95% CI: 16%-52%). pCR was achieved in 4 (10%) and 5 (18%) patients, and pNCR in 17 (43%) and 4 (14%) patients. In immunohistochemical analysis, most DC 3 cells were not apoptotic. The most common grade ≥3 toxic effects in the P + CRT/CRT arm were diarrhea (10%/6%) and anastomotic leakage (15%/4%). Conclusions The addition of panitumumab to neoadjuvant CRT in patients with KRAS wild-type LARC resulted in a high pNC/CR rate, mostly grade 3 DC. The results of both treatment arms exceeded prespecified thresholds. The addition of panitumumab increased toxicit

Were Fertile Crescent crop progenitors higher yielding than other wild species that were never domesticated?

During the origin of agriculture in the Fertile Crescent, the broad spectrum of wild plant species exploited by hunter-gatherers narrowed dramatically. The mechanisms responsible for this specialization and the associated domestication of plants are intensely debated. We investigated why some species were domesticated rather than others, and which traits they shared. We tested whether the progenitors of cereal and pulse crops, grown individually, produced a higher yield and less chaff than other wild grasses and legumes, thereby maximizing the return per seed planted and minimizing processing time. We compared harvest traits of species originating from the Fertile Crescent, including those for which there is archaeological evidence of deliberate collection. Unexpectedly, wild crop progenitors in both families had neither higher grain yield nor, in grasses, less chaff, although they did have larger seeds. Moreover, small-seeded grasses actually returned a higher yield relative to the mass of seeds sown. However, cereal progenitors had threefold fewer seeds per plant, representing a major difference in how seeds are packaged on plants. These data suggest that there was no intrinsic yield advantage to adopting large-seeded progenitor species as crops. Explaining why Neolithic agriculture was founded on these species, therefore, remains an important unresolved challenge

Robustness assessment of the ‘cooperation under resource pressure’ (CURP) model: Insights on resource availability and sharing practices among hunter-gatherers

A well-known challenge in archaeological research is the exploration of the social mechanisms that hunter-gatherers may have implemented throughout history to deal with changes in resource availability. The agent-based model (ABM) ‘cooperation under resource pressure’ (CURP) was conceived to explore food stress episodes in societies lacking a food preservation technology. It was particularly aimed at understanding how cooperative behaviours in the form of food sharing practices emerge, increase and may become the prevailing strategy in relation to changes in resource availability and expectancy of reciprocity. CURP’s main outcome is the identification of three regimes of behaviour depending on the stress level. In this work, the model’s robustness to the original selection mechanism (random tournament) is assessed, as different dynamics can lead to different persistent regimes. For that purpose, three other selection mechanisms are implemented and evaluated, to identify the prevailing states of the system. Results show that the three regimes are robust irrespective of the analysed dynamics. We consequently examine in more detail the long-term archaeological implications that these results may have.Spanish Ministry of Economy and Competitiveness (former Ministry of Science and Innovation): SimulPast Project (CSD2010- 00034 CONSOLIDER-INGENIO 2010), HAR2009-06996 and CULM Project (HAR2016- 77672-P); from the Argentine National Scientific and Technical Research Council (CONICET): Project PIP-0706; from the Wenner-Gren Foundation for Anthropological Research: Project GR7846; from the project H2020 FET OPEN RIA IBSEN/662725 and from the European Social Fund as one of the authors is the recipient of a predoctoral grant from the Department of Education of Junta de Castilla y León (Spain)

Tackling increased risks in older adults with intellectual disability and epilepsy: data from a national multicentre cohort study

Purpose: People with intellectual disabilities (ID) suffer multimorbidity, polypharmacy and excess mortality at a younger age than general population. Those with ID and epilepsy are at higher risk of worse clinical outcomes than their peers without epilepsy. In the ID population the health profile of those aged ≥40 years can be compared to those aged over 65 in the general population. To date there is limited data available to identify clinical characteristics and risk factors in older adults (≥40 years) with ID and epilepsy. / Methods: The Epilepsy in ID National Audit (Epi-IDNA) identified 904 patients with ID and epilepsy from 10 sites in England and Wales. This subsequent analysis of the Epi-IDNA cohort compared the 405 adults over 40 years with 499 adults ≥18 years aged under 40 years. Comparison was made between clinical characteristics and established risk factors using the Sudden Unexpected Death in Epilepsy (SUDEP) and Seizure Safety Checklist. / Results: The older adults’ cohort had significantly higher levels of co-morbid physical health conditions, mental health conditions, anti-seizure medications (median 5), and antipsychotics compared to the younger cohort. The older group were significantly less likely to be diagnosed with a co-morbid neurodevelopmental disorder, and to have an epilepsy care plan. / Conclusion: This is the largest study to date focused on adults with ID and epilepsy over 40 years. The ≥40 years cohort compared to the younger group has higher levels of clinical risk factors associated with multi-morbidity, potential iatrogenic harm and premature mortality with worse clinical oversight mechanisms

Electronically preresonant stimulated Raman scattering microscopy in the visible

We report an experimental scheme for stimulated Raman scattering (SRS) microscopy with excitation in the visible spectral region. This allows electronically preresonant (epr) SRS microscopy of a broad range of chromophores with sensitivities as low as 1 μM. Our experiment is based on two synchronously near-infrared pumped optical parametric oscillators (OPO). One of the outputs is modulated at a fourth of the repetition rate with a novel broadband electro-optical modulator. Using a combination of spectral focusing and tuning of the OPO, we show the recording of epr-SRS spectra over the whole range of molecular vibrations at a speed up to 20 times faster than classical wavelength tuning. The imaging capabilities of this setup are demonstrated with material scientific and cellular samples

Human biogeography and faunal exploitation in Diamante River basin, central western Argentina

A biogeographic model used to describe human peopling of southern Mendoza, central western Argentina, proposed an intensification process activated by an increase in population growth rate during the Late Holocene. During this process, high-ranked resources at the surroundings of residential camps were depleted, and hunter–gatherers broadened their diet by incorporating a larger number of low-ranked prey and domesticated plant resources. In this paper, we evaluate an alternative hypothesis, focusing on zooarchaeological data from the Diamante River basin. The results show that faunal resource intensification does not appear to have occurred in the Diamante River basin during the Late Holocene. Faunal consumption in Diamante River basin mainly reflects the local fauna in each ecological zone. The data do not show a lack of higher ranked resources. We suggest it is more likely that the demographic increase was not significant enough to cause an impact on the faunal resources. The archaeological evidence should be improved and analysed in smaller scales to continue with the intensification debate.Fil: Otaola, Clara. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Mendoza. Instituto Argentino de Nivología, Glaciología y Ciencias Ambientales. Provincia de Mendoza. Instituto Argentino de Nivología, Glaciología y Ciencias Ambientales. Universidad Nacional de Cuyo. Instituto Argentino de Nivología, Glaciología y Ciencias Ambientales; ArgentinaFil: Giardina, Miguel Angel. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Mendoza. Instituto Argentino de Nivología, Glaciología y Ciencias Ambientales. Provincia de Mendoza. Instituto Argentino de Nivología, Glaciología y Ciencias Ambientales. Universidad Nacional de Cuyo. Instituto Argentino de Nivología, Glaciología y Ciencias Ambientales; ArgentinaFil: Franchetti, Fernando Ricardo. University of Pittsburgh at Johnstown; Estados Unidos. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentin

Review of the methods of determination of directed connectivity from multichannel data

The methods applied for estimation of functional connectivity from multichannel data are described with special emphasis on the estimators of directedness such as directed transfer function (DTF) and partial directed coherence. These estimators based on multivariate autoregressive model are free of pitfalls connected with application of bivariate measures. The examples of applications illustrating the performance of the methods are given. Time-varying estimators of directedness: short-time DTF and adaptive methods are presented