Chemoprevention of lung cancer—from biology to clinical reality

Lung cancer is the commonest cause of cancer death in developed countries and throughout the world. Cigarette smoking is the main risk factor for lung cancer and ex-smokers today comprise ∼50% of all new lung cancer cases. Chemoprevention builds on the concepts of field of cancerization and multistep carcinogenesis and can be defined as the use of natural or chemical compounds to prevent, inhibit or reverse the process of carcinogenesis. So far, chemoprevention studies in lung cancer have failed to reduce lung cancer mortality. New developments in biotechnology have made it possible to define more accurately high-risk populations, make earlier diagnosis possible, and allow more specific targeted therapies to be developed. Both the development and validation of biomarkers, for the selection of high-risk study populations and for response evaluation in chemoprevention studies, are important for the faster turnover of studies evaluating new agents. This article reviews the current status and describes the perspectives for new approaches in the chemoprevention of lung cance

SAKK 24/09: safety and tolerability of bevacizumab plus paclitaxel vs. bevacizumab plus metronomic cyclophosphamide and capecitabine as first-line therapy in patients with HER2-negative advanced stage breast cancer - a multicenter, randomized phase III trial.

BACKGROUND: Adding bevacizumab to chemotherapy improves response rates and progression-free survival (PFS) in metastatic breast cancer (mBC). We aimed to demonstrate decreased toxicity with metronomic chemotherapy/bevacizumab compared with paclitaxel/bevacizumab. METHODS: This multicenter, randomized phase III trial compared bevacizumab with either paclitaxel (arm A) or daily oral capecitabine-cyclophosphamide (arm B) as first-line treatment in patients with HER2-negative advanced breast cancer. The primary endpoint was the incidence of selected grade 3-5 adverse events (AE) including: febrile neutropenia, infection, sensory/motor neuropathy, and mucositis. Secondary endpoints included objective response rate, disease control rate, PFS, overall survival (OS), quality of life (QoL), and pharmacoeconomics. The study was registered prospectively with ClinicalTrials.gov, number NCT01131195 on May 25, 2010. RESULTS: Between September 2010 and December 2012, 147 patients were included at 22 centers. The incidence of primary endpoint-defining AEs was similar in arm A (25 % [18/71]; 95 % CI 15-35 %) and arm B (24 % [16/68]; 95 % CI 13-34 %; P = 0.96). Objective response rates were 58 % (42/73; 95 % CI 0.46-0.69) and 50 % (37/74; 95 % CI 0.39-0.61) in arms A and B, respectively (P = 0.45). Median PFS was 10.3 months (95 % CI 8.7-11.3) in arm A and 8.5 months (95 % CI 6.5-11.9) in arm B (P = 0.90). Other secondary efficacy endpoints were not significantly different between study arms. The only statistically significant differences in QoL were less hair loss and less numbness in arm B. Treatment costs between the two arms were equivalent. CONCLUSION: This trial failed to meet its primary endpoint of a reduced rate of prespecified grade 3-5 AEs with metronomic bevacizumab, cyclophosphamide and capecitabine

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

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

Prognostic value of different CT measurements in early therapy response evaluation in patients with metastatic colorectal cancer

OBJECTIVES: Patients with advanced stage colorectal carcinoma (CRC) display hepatic metastases on initial staging in up to 20% of cases. The effectiveness of chemotherapy is generally evaluated by computed tomography (CT) imaging using standardized criteria (RECIST). However, RECIST is not always optimal, and other criteria have been shown to correlate with pathologic response and overall survival. The aim of this study was to evaluate the prognostic value of different CT measurement for response assessment after initiation of chemotherapy in patients with synchronous colorectal cancer liver metastases. METHODS: Fifty-five patients with CRC and synchronous hepatic metastases were evaluated retrospectively at 2 academic centers. Different size, volume, ratio and attenuation parameters were determined at baseline and after 3 cycles of chemotherapy. The prognostic value of baseline measurements and of the change between baseline and second measurements was analyzed using Kaplan-Meier estimates. RESULTS: Median time to progression was 279 days, median overall survival was 704 days. In this selective patient population, neither a significant prognostic value of initial baseline CT parameters nor a prognostic value of the change between the first and the second CT measurements was found. CONCLUSION: Initial morphological response assessment using different CT measurements has no prognostic value concerning time to progression or overall survival in patients with synchronous colorectal liver metastases

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

Emergence and Evolution of Cooperation Under Resource Pressure

We study the influence that resource availability has on cooperation in the context of hunter-gatherer societies. This paper proposes a model based on archaeological and ethnographic research on resource stress episodes, which exposes three different cooperative regimes according to the relationship between resource availability in the environment and population size. The most interesting regime represents moderate survival stress in which individuals coordinate in an evolutionary way to increase the probabilities of survival and reduce the risk of failing to meet the minimum needs for survival. Populations self-organise in an indirect reciprocity system in which the norm that emerges is to share the part of the resource that is not strictly necessary for survival, thereby collectively lowering the chances of starving. Our findings shed further light on the emergence and evolution of cooperation in hunter-gatherer societies.Spanish Ministry of Science and Innovation Project CSD2010-00034 (SimulPast CONSOLIDER-INGENIO 2010) and HAR2009-06996; from the Argentine National Scientific and Technical Research Council (CONICET): Project PIP-0706; from the Wenner-Gren Foundation for Anthropological Research: Project GR7846; and from the project H2020 FET OPEN RIA IBSEN/66272

Women’s subsistence strategies predict fertility across cultures, but context matters

While it is commonly assumed that farmers have higher, and foragers lower, fertility compared to populations practicing other forms of subsistence, robust supportive evidence is lacking. We tested whether subsistence activities—incorporating market integration—are associated with fertility in 10,250 women from 27 small-scale societies and found considerable variation in fertility. This variation did not align with group-level subsistence typologies. Societies labeled as “farmers” did not have higher fertility than others, while “foragers” did not have lower fertility. However, at the individual level, we found strong evidence that fertility was positively associated with farming and moderate evidence of a negative relationship between foraging and fertility. Markers of market integration were strongly negatively correlated with fertility. Despite strong cross-cultural evidence, these relationships were not consistent in all populations, highlighting the importance of the socioecological context, which likely influences the diverse mechanisms driving the relationship between fertility and subsistence

Role of retinoic receptors in lung carcinogenesis

Several in vitro and in vivo studies have examined the positive and negative effects of retinoids (vitamin A analogs) in premalignant and malignant lesions. Retinoids have been used as chemopreventive and anticancer agents because of their pleiotropic regulator function in cell differentiation, growth, proliferation and apoptosis through interaction with two types of nuclear receptors: retinoic acid receptors and retinoid X receptors. Recent investigations have gradually elucidated the function of retinoids and their signaling pathways and may explain the failure of earlier chemopreventive studies