Treatment-Related Death in Patients with Small-Cell Lung Cancer in Phase III Trials over the Last Two Decades

Introduction

Treatment-related death (TRD) remains a serious problem in small-cell lung cancer (SCLC), despite recent improvements in supportive care. However, few studies have formally assessed time trends in the proportion of TRD over the past two decades. The aim of this study was to determine the frequency and pattern of TRD over time.

Methods

We examined phase 3 trials conducted between 1990 and 2010 to address the role of systemic treatment for SCLC. The time trend was assessed using linear regression analysis.

Results

In total, 97 trials including nearly 25,000 enrolled patients were analyzed. The overall TRD proportion was 2.95%. Regarding the time trend, while it was not statistically significant, it tended to decrease, with a 0.138% decrease per year and 2.76% decrease per two decades. The most common cause of death was febrile neutropenia without any significant time trend in its incidence over the years examined (p = 0.139). However, deaths due to febrile neutropenia as well as all causes in patients treated with non-platinum chemotherapy increased significantly (p = 0.033).

Conclusions

The overall TRD rate has been low, but not negligible, in phase III trials for SCLC over the past two decades.     

Dendritic Cell-Based Immunotherapy for Solid Tumors

As a treatment for solid tumors, dendritic cell (DC)-based immunotherapy has not been as effective as expected. Here, we review the reasons underlying the limitations of DC-based immunotherapy for solid tumors and ask what can be done to improve immune cell-based cancer therapies. Several reports show that, rather than a lack of immune induction, the limited efficacy of DC-based immunotherapy in cases of renal cell carcinoma (RCC) likely results from inhibition of immune responses by tumor-secreted TGF-β and an increase in the number of regulatory T (Treg) cells in and around the solid tumor. Indeed, unlike DC therapy for solid tumors, cytotoxic T lymphocyte (CTL) responses induced by DC therapy inhibit tumor recurrence after surgery; CTL responses also limit tumor metastasis induced by additional tumor-challenge in RCC tumor-bearing mice. Here, we discuss the mechanisms underlying the poor efficacy of DC-based therapy for solid tumors and stress the need for new and improved DC immunotherapies and/or combination therapies with killer cells to treat resistant solid tumors.     

Nanoparticle Ligand Presentation for Targeting Solid Tumors

Among the many scientific advances to come from the study of nanoscience, the development of ligand-targeted nanoparticles to eliminate solid tumors is predicted to have a major impact on human health. There are many reports describing novel designs and testing of targeted nanoparticles to treat cancer. While the principles of the technology are well demonstrated in controlled lab experiments, there are still many hurdles to overcome for the science to mature into truly efficacious targeted nanoparticles that join the arsenal of agents currently used to treat cancer in humans. One of these hurdles is overcoming unwanted biodistribution to the liver while maximizing delivery to the tumor. This almost certainly requires advances in both nanoparticle stealth technology and targeting. Currently, it continues to be a challenge to control the loading of ligands onto polyethylene glycol (PEG) to achieve maximal targeting. Nanoparticle cellular uptake and subcellular targeting of genes and siRNA also remain a challenge. This review examines the types of ligands that have been most often used to target nanoparticles to solid tumors. As the science matures over the coming decade, careful control over ligand presentation on nanoparticles of precise size, shape, and charge will likely play a major role in achieving success.KEY WORDS: cancer, nanoparticle, targeted delivery     

Obesity Research in Canada: Literature Overview of the Last 3 Decades

Objective: To identify research published on obesity in Canada, to explore the range of areas studied, and to identify gaps and areas that merit future research attention. Research Methods and Procedures: Medline and International Pharmaceutical Abstracts databases were searched from 1970 onwards. Original articles were identified and categorized by areas of interest. Results: A total of 1186 relevant articles were identified: 17, 136, 687, and 346 articles during the 1970s, 1980s, 1990s, and 2000 to 2003, respectively. Of the articles, 816 were considered original studies and accepted for this analysis. Twelve research areas were identified: basic science involving animal experiments (29%), human experiments (16%), populations surveys (14%), obesity‐related comorbidities (13%), diagnostic/surgical issues (11%), nonpharmacological approaches (7%), drug‐related issues (4%), anthropometrics (2%), impact of weight loss (2%), cost/healthcare use (1%), attitudes/perceptions (0.9%), and models/procedures (0.5%). Two‐thirds of all research was conducted in Quebec (34%) and Ontario (33%). Discussion: Given the multifactorial nature of obesity, Canadian obesity research covers a broad range of areas with a predominance of basic science but lesser emphasis on community and primary care studies. Furthermore, there was a paucity of research on either clinical management of medical conditions in obese patients or clinical aspects that go beyond weight loss. Thus, although Canada appears well represented in basic research, more attention to exploration of clinical issues and healthcare delivery for obese patients appears warranted.     

Stereotactic Body Radiation Therapy for Primary and Metastatic Liver Tumors

OBJECTIVES: The full potential of stereotactic body radiation therapy (SBRT), in the treatment of unresectable intrahepatic malignancies, has yet to be realized as our experience is still limited. Thus, we evaluated SBRT outcomes for primary and metastatic liver tumors, with the goal of identifying factors that may aid in optimization of therapy. METHODS: From2005 to 2010, 62 patients with 106 primary and metastatic liver tumors were treated with SBRT to a median biologic effective dose (BED) of 100 Gy (42.6-180). The majority of patients received either three (47%) or five fractions (48%). Median gross tumor volume (GTV) was 8.8 cm³ (0.2-222.4). RESULTS: With a median followup of 18 months (0.46-46.8), freedom from local progression (FFLP) was observed in 97 of 106 treated tumors, with 1- and 2-year FFLP rates of 93% and 82%. Median overall survival (OS) for all patients was 25.2 months, with 1- and 2-year OS of 81%and 52%. Neither BED nor GTV significantly predicted for FFLP. Local failure was associated with a higher risk of death [hazard ratio (HR) = 5.1, P = .0007]. One Child-Pugh Class B patient developed radiationinduced liver disease. There were no other significant toxicities. CONCLUSIONS: SBRT provides excellent local control for both primary and metastatic liver lesions with minimal toxicity. Future studies should focus on appropriate selection of patients and on careful assessment of liver function to maximize both the safety and efficacy of treatment.     

CAR-T联合疗法治疗实体瘤的研究进展

CAR-T疗法(chimeric antigen receptor T-cell immunotherapy)即嵌合抗原受体T细胞免疫疗法,是目前肿瘤免疫治疗中较有潜力的策略之一^[1],已成功应用于多种血液肿瘤的治疗。但CAR-T疗法在治疗实体瘤领域进展缓慢,存在肿瘤微环境的限制、细胞因子释放综合征以及严重的脱靶效应等诸多挑战^[2]。与单一靶向治疗相比,CAR-T联合疗法为改进肿瘤治疗方法提供了新的方向。综述目前常用的CAR-T联合治疗策略,针对CAR-T疗法在实体瘤治疗领域面临的主要挑战,探讨提高CAR-T疗效的潜在方案。     

Germline Features Associated with Immune Infiltration in Solid Tumors

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Suicide Gene Therapy for Intrinsically Drug Resistant Solid Tumors

Abstract

The failure of available anticancer drugs to cure the common human solid tumors is thought to be caused by their poor selective toxicity. As demonstrated herein, suicide gene therapy offers the potential to improve selective toxicity.     

多尺度的光声显微镜用于癌细胞及实体瘤成像

多尺度显微成像系统(M-PAM)被发展,并被用于成像从癌细胞到实体肿瘤的多尺度生物结构.该装置由二维运动平台,扫描振镜,物镜,聚焦超声换能器组成,其横向分辨率达到3 μm.结果显示该系统可以对体外培养黑色素瘤细胞与体内的黑色素瘤进行无标记成像.基于具有靶向性的探针,M-PAM系统可以对体外培养的U87-MG肿瘤细胞以及体内U87-MG实体肿瘤进行成像.综上所述,M-PAM系统将是研究肿瘤的有力工具.     

A Superior Technique for Culturing and Karyotyping Solid Tumors

We have devised a new cell culture method where two types of culture plates made of normal tissue culture plastic (NTCP) and Primaria(TM), and two media, RPMI-1640 and a serum-free media LHC-9(TM), are used in combination with an in situ harvest. Multiple culture conditions in combination with in situ harvest has yielded many more clones for karyotyping than was possible with previous methods. Cells were cultured in 60 mm Petri plates instead of flasks and harvested in situ. Chromosome banding was performed using a highly purified trypsin "Enzar-T(TM)" and Leishman stain instead of ordinary trypsin and Giemsa stain. These modifications have increased the number of clones retrieved, rate of culture success, and quality of karyotypes in solid tumors.     

Candidaemia Mortality Has not Changed Over the Last 2 Decades in Brazil

Mycopathologia - Despite advances in fungal diagnostics and antifungal therapy, mortality associated with candidaemia remains very high, particularly in developing countries. In this study, we...     

The Global Pattern of Urbanization and Economic Growth: Evidence from the Last Three Decades

The relationship between urbanization and economic growth has been perplexing. In this paper, we identify the pattern of global change and the correlation of urbanization and economic growth, using cross-sectional, panel estimation and geographic information systems (GIS) methods. The analysis has been carried out on a global geographical scale, while the timescale of the study spans the last 30 years. The data shows that urbanization levels have changed substantially during these three decades. Empirical findings from cross-sectional data and panel data support the general notion of close links between urbanization levels and GDP per capita. However, we also present significant evidence that there is no correlation between urbanization speed and economic growth rate at the global level. Hence, we conclude that a given country cannot obtain the expected economic benefits from accelerated urbanization, especially if it takes the form of government-led urbanization. In addition, only when all facets are taken into consideration can we fully assess the urbanization process.     

Modeling the Transfer of Drug Resistance in Solid Tumors

ABC efflux transporters are a key factor leading to multidrug resistance in cancer. Overexpression of these transporters significantly decreases the efficacy of anti-cancer drugs. Along with selection and induction, drug resistance may be transferred between cells, which is the focus of this paper. Specifically, we consider the intercellular transfer of P-glycoprotein (P-gp), a well-known ABC transporter that was shown to confer resistance to many common chemotherapeutic drugs. In a recent paper, Durán et al. (Bull Math Biol 78(6):1218–1237, 2016) studied the dynamics of mixed cultures of resistant and sensitive NCI-H460 (human non-small lung cancer) cell lines. As expected, the experimental data showed a gradual increase in the percentage of resistance cells and a decrease in the percentage of sensitive cells. The experimental work was accompanied with a mathematical model that assumed P-gp transfer from resistant cells to sensitive cells, rendering them temporarily resistant. The mathematical model provided a reasonable fit to the experimental data. In this paper, we develop a new mathematical model for the transfer of drug resistance between cancer cells. Our model is based on incorporating a resistance phenotype into a model of cancer growth (Greene et al. in J Theor Biol 367:262–277, 2015). The resulting model for P-gp transfer, written as a system of integro-differential equations, follows the dynamics of proliferating, quiescent, and apoptotic cells, with a varying resistance phenotype. We show that this model provides a good match to the dynamics of the experimental data of Durán et al. (2016). The mathematical model shows a better fit when resistant cancer cells have a slower division rate than the sensitive cells.     

三十年来中国植物生态学和地植物学的回顾和展望

本文就以下几方面对我国植物生态学和地植物学作了回顾与展望。一、回顾：1．亚热带和热带森林区的植被研究。2．温带森林区的植被研究。3．温带草原区的植被研究。4．温带荒漠区的植被研究。5．青藏高寒高原区的植被研究。6．中国植被及其地理、分区和植被图研究。7．环境植物学的研究等。二,展望1．植被基本理论的研究2．植被图志的编制和植被制图学研究 3．栽培植物群落和经济植物生态学特性研究4．实验群落学和植物生理生态学研究5．陆地生态系统的结构和功能的研究6．环境保护的植物生态学研究7．植物和植物群落指示性研究     

Rice Genomics: over the Past Two Decades and into the Future

Domestic rice (Oryza sativa L.) is one of the most important cereal crops, feeding a large number of worldwide populations. Along with various high-throughput genome sequencing projects, rice genomics has been making great headway toward direct field applications of basic research advances in understanding the molecular mechanisms of agronomical traits and utilizing diverse germplasm resources. Here, we briefly review its achievements over the past two decades and present the potential for its bright future.     

Olfaction in People with Down Syndrome: A Comprehensive Assessment across Four Decades of Age

Background

Down syndrome (DS) shows neuropathology similar to Alzheimer disease, which presents olfactory impairment. Previous work showed olfactory impairment in DS, but a comprehensive evaluation of olfactory function in DS is lacking.

Methods

We investigated a large number (n = 56; M = 31, F = 25) DS participants (age range18-57y) using the “Sniffin’ Sticks” Extended test. This comprises three subtests (threshold, discrimination, and identification) yielding a global score (TDI) defining normosmia, hyposmia, and functional anosmia. To the best of our knowledge, this is the second largest group of DS people investigated for olfactory function ever. Age- and sex matched euploid individuals (n = 53) were the control.

Results

In DS, TDI was lower (16.7±5.13 vs. 35.4±3.74; P<0.001), with DS people performing worse in any subtests (P<0.001 for all); 27 DS participants showed functional anosmia (i.e., TDI<16). In DS, age was weakly and negatively correlated with TDI (r = -0.28, P = 0.036) and identification (r = -0.34, P = 0.012). When participants were stratified in young adults (18-29y) and older adults (30-61y), a significant effect of age was found for identification in both DS (young adults, 8.3±2.58; older adults, 6.9±2.99; P = 0.031) and control (young-adult, 14.3±1.18, older adult, 13.0±1.54; P = 0.016).

Conclusion

Olfactory function is overall severely impaired in DS people and may be globally impaired at relatively young age, despite of reportedly normal smell. However, specificity of this olfactory profile to DS should be considered with some caution because cognition was not evaluated in all DS participants and comparison with a control group of non-DS individuals having cognitive disabilities was lacking. Further study is required to longitudinally assess olfactory dysfunction in DS and to correlate it with brain pathology.     

Evolution of Extensively Drug-Resistant Tuberculosis over Four Decades: Whole Genome Sequencing and Dating Analysis of Mycobacterium tuberculosis Isolates from KwaZulu-Natal

BackgroundThe continued advance of antibiotic resistance threatens the treatment and control of many infectious diseases. This is exemplified by the largest global outbreak of extensively drug-resistant (XDR) tuberculosis (TB) identified in Tugela Ferry, KwaZulu-Natal, South Africa, in 2005 that continues today. It is unclear whether the emergence of XDR-TB in KwaZulu-Natal was due to recent inadequacies in TB control in conjunction with HIV or other factors. Understanding the origins of drug resistance in this fatal outbreak of XDR will inform the control and prevention of drug-resistant TB in other settings. In this study, we used whole genome sequencing and dating analysis to determine if XDR-TB had emerged recently or had ancient antecedents.ConclusionsIn the first whole genome-based analysis of the emergence of drug resistance among clinical isolates of M. tuberculosis, we show that the ancestral precursor of the LAM4 XDR outbreak strain in Tugela Ferry gained mutations to first-line drugs at the beginning of the antibiotic era. Subsequent accumulation of stepwise resistance mutations, occurring over decades and prior to the explosion of HIV in this region, yielded MDR and XDR, permitting the emergence of compensatory mutations. Our results suggest that drug-resistant strains circulating today reflect not only vulnerabilities of current TB control efforts but also those that date back 50 y. In drug-resistant TB, isoniazid resistance was overwhelmingly the initial resistance mutation to be acquired, which would not be detected by current rapid molecular diagnostics employed in South Africa that assess only rifampicin resistance.     

The Clinical Presentation of Primary Hyperparathyroidism: A Southern European Perspective Over the Last 2 Decades

Objective: The clinical presentation of primary hyperparathyroidism (PHPT) has changed widely in developed countries in the last few decades. We evaluated its variations in our series over a 20-year period (i.e., 1997–2016).Methods: A retrospective survey was conducted in our series of 364 well-characterized consecutive patients, arbitrarily divided into 4 consecutive 5-year periods at diagnosis.Results: In the overall series, only estimated glomerular function (eGFR) and urinary calcium (UCa) showed a significant upward trend (P = .032 and .039, respectively), whereas demographic and clinical characteristics were stable. The UCa upward trend was also confirmed for the subgroup of symptomatic patients (P = .013). No difference was observed in the demographic, clinical, or biochemical characteristics of asymptomatic patients or in the fraction of patients meeting surgical criteria.Conclusion: The clinical presentation of PHPT was stable over 20 years in our large series.Abbreviations: Ca = calcium; eGFR = estimated glomerular filtration rate; 25OHD = 25-hydroxyvitamin D; PHPT = primary hyperparathyroidism; PTH = parathyroid hormone; UCa = urinary calcium     

Identification of Genes Associated with Local Aggressiveness and Metastatic Behavior in Soft Tissue Tumors

Soft tissue tumors represent a group of neoplasia with different histologic and biological presentations varying from benign, locally confined to very aggressive and metastatic tumors. The molecular mechanisms responsible for such differences are still unknown. The understanding of these molecular alterations mechanism will be critical to discriminate patients who need systemic treatment from those that can be treated only locally and could also guide the development of new drugs'' against this tumors. Using 102 tumor samples representing a large spectrum of these tumors, we performed expression profiling and defined differentially expression genes that are likely to be involved in tumors that are locally aggressive and in tumors with metastatic potential. We described a set of 12 genes (SNRPD3, MEGF9, SPTAN-1, AFAP1L2, ENDOD1, SERPIN5, ZWINTAS, TOP2A, UBE2C, ABCF1, MCM2, and ARL6IP5) showing opposite expression when these two conditions were compared. These genes are mainly related to cell-cell and cell-extracellular matrix interactions and cell proliferation and might represent helpful tools for a more precise classification and diagnosis as well as potential drug targets.     

Elastic Free Energy Drives the Shape of Prevascular Solid Tumors

It is well established that the mechanical environment influences cell functions in health and disease. Here, we address how the mechanical environment influences tumor growth, in particular, the shape of solid tumors. In an in vitro tumor model, which isolates mechanical interactions between cancer tumor cells and a hydrogel, we find that tumors grow as ellipsoids, resembling the same, oft-reported observation of in vivo tumors. Specifically, an oblate ellipsoidal tumor shape robustly occurs when the tumors grow in hydrogels that are stiffer than the tumors, but when they grow in more compliant hydrogels they remain closer to spherical in shape. Using large scale, nonlinear elasticity computations we show that the oblate ellipsoidal shape minimizes the elastic free energy of the tumor-hydrogel system. Having eliminated a number of other candidate explanations, we hypothesize that minimization of the elastic free energy is the reason for predominance of the experimentally observed ellipsoidal shape. This result may hold significance for explaining the shape progression of early solid tumors in vivo and is an important step in understanding the processes underlying solid tumor growth.