Surgically resectable nonsmall cell lung cancer: a contemporary approach.

New treatment paradigms for resectable nonsmall cell lung cancer (NSCLC), with an emphasis on personalised care and a multidisciplinary approach, have significantly improved patient outcomes. The incorporation of immune checkpoint inhibitors into neoadjuvant, perioperative and adjuvant treatment algorithms is reshaping the standard of care for resectable NSCLC. Adjuvant targeted therapy trials have also paved the way for a much-needed personalised approach for patients with actionable genomic alterations. Innovative surgical techniques and judicious use of postoperative radiotherapy may mitigate the toxicity associated with a multimodality approach. Amid the many new treatment options, questions remain about the best approach to consider for each patient. Measurement of minimal residual disease and achievement of pathological complete response are emerging biomarkers of interest to help further refine treatment selection. This review summarises the current management of resectable NSCLC, focusing on ongoing and recent advances in surgical approaches, the role of postoperative radiotherapy and the rapidly changing field of systemic therapies.

Supporting cognitive catch-up: The effects of cluster-randomized psychosocial stimulation interventions on preterm low birthweight children in rural China.

Improved survival of preterm low birthweight (LBW) infants due to advances in neonatal care has brought issues such as postnatal development trajectories to the foreground. This study pools evidence from three cluster-randomized experiments evaluating community-based psychosocial stimulation programs conducted from 2014 to 2017 that included 3571 rural Chinese children aged 6-24 months (51.1% male, 96.2% Han Chinese). The risk of severe cognitive delay was found to be 26.5 percentage points higher for preterm LBW children than for their peers at age 2.5, with a prevalence rate of 48.3%. Results show that psychosocial stimulation interventions can improve child cognitive development at scale, with beneficial impacts on child cognition disproportionately larger for preterm LBW children, helping them to catch up developmentally.

A network analysis of positive developmental assets of Hong Kong school-age children during the Covid-19 pandemic.

The ongoing COVID19 pandemic is having detrimental effects on the mental and emotional well-being of many adults and children. It is relevant therefore to explore the combination of personal strengths and attributes that can help an individual develop resilience to such stress. Little is known about how psychological strength assets such as social connectedness, grit, hope, life meaning, and life satisfaction are inter-related, and if certain factors play a central role. This study involved a sample of 1,405 school-aged children in Hong Kong (50% female) from seven schools that participated in an online survey of psychological strengths. Data were analyzed by constructing a psychological network that found strength factors are inter-connected, and that 'school connectedness' and 'agency thinking' are central to the network. The information gained can be of value in any schools that are planning to provide strength-based interventions to help students maintain their psychological well-being during and after the COVID-19 pandemic.

Gonorrhea and Chlamydia Rates Among 12- to 24-Year-Old Patients in an Urban Health System.

BACKGROUND: Chlamydia trachomatis (CT) and Neisseria gonorrhoeae (GC) infection rates continue to rise. Screening guidelines have largely focused on sexually active female individuals and men who have sex with men populations. Health care system testing and infection rates, particularly among heterosexual male individuals, are poorly understood. Our aim was to evaluate CT and GC testing and prevalence among 12- to 24-year-old patients in an urban federally qualified health center system. METHODS: This retrospective study analyzed electronic health record data from 2017 to 2019 in a large system of federally qualified health centers in Denver, CO. Abstracted data included demographics, sexual activity, sexual orientation, and laboratory results. χ2 Tests were used to evaluate differences between groups. RESULTS: Of the 44,021 patients included, 37.6% were tested, 15.0% were positive for CT, and 3.4% were positive for GC. Heterosexual male patients had a testing rate of 22.8% and positivity rates of CT and GC at 13.1% and 3.0%, respectively. Among tested patients documented as not sexually active, 7.5% were positive for CT. Multiple or reinfections were detected in 29% of patients. CONCLUSIONS: This study shows low testing rates and high rates of CT and GC infections among all patients, including heterosexual male patients and those documented as not sexually active. Improved screening of these populations in the primary care setting may be key to combating the sexually transmitted disease epidemic.

Pre- and post-operative anti-PD-L1 plus anti-angiogenic therapies in mouse breast or renal cancer models of micro- or macro-metastatic disease.

BACKGROUND: There are phase 3 clinical trials underway evaluating anti-PD-L1 antibodies as adjuvant (postoperative) monotherapies for resectable renal cell carcinoma (RCC) and triple-negative breast cancer (TNBC); in combination with antiangiogenic VEGF/VEGFR2 inhibitors (e.g., bevacizumab and sunitinib) for metastatic RCC; and in combination with chemotherapeutics as neoadjuvant (preoperative) therapies for resectable TNBC. METHODS: This study investigated these and similar clinically relevant drug combinations in highly translational preclinical models of micro- and macro-metastatic disease that spontaneously develop after surgical resection of primary kidney or breast tumours derived from orthotopic implantation of murine cancer cell lines (RENCAluc or EMT-6/CDDP, respectively). RESULTS: In the RENCAluc model, adjuvant sunitinib plus anti-PD-L1 improved overall survival compared to either drug alone, while the same combination was ineffective as early therapy for unresected primary tumours or late-stage therapy for advanced metastatic disease. In the EMT-6/CDDP model, anti-PD-L1 was highly effective as an adjuvant monotherapy, while its combination with paclitaxel chemotherapy (with or without anti-VEGF) was most effective as a neoadjuvant therapy. CONCLUSIONS: Our preclinical data suggest that anti-PD-L1 plus sunitinib may warrant further investigation as an adjuvant therapy for RCC, while anti-PD-L1 may be improved by combining with chemotherapy in the neoadjuvant but not the adjuvant setting of treating breast cancer.

Treating anaplastic lymphoma kinase (ALK) fusion-driven metastatic non-small cell lung cancer (NSCLC) with alectinib through pregnancy.

Management of cancer during pregnancy requires careful consideration of risks and benefits from maternal and fetal perspectives. For advanced lung adenocarcinomas, with no targetable driver mutations, there is evidence-based guidance on the use of carboplatin-paclitaxel chemotherapy after first trimester. In contrast, for epidermal growth factor receptor (EGFR)-mutated or anaplastic lymphoma kinase (ALK)-rearranged metastatic lung adenocarcinomas, there is a paucity of clinical data on the safety of EGFR and ALK tyrosine kinase inhibitors to mother and fetus for official guidelines to recommend the use of these otherwise-first-line therapies in pregnancy. Considering this knowledge gap, we present a case of a young gravida 1 para 0 (G1P0) woman who continued alectinib 300 mg oral two times per day for ALK-rearranged metastatic lung adenocarcinoma throughout all 36 weeks of her pregnancy and delivered a healthy baby at term via caesarean section (C-section).

Kinetic Profiling of RAS Mutations With Circulating Tumor DNA in the Canadian Cancer Trials Group CO.26 Trial Suggests the Loss of RAS Mutations in Neo-RAS-Wildtype Metastatic Colorectal Cancer Is Transient.

PURPOSE: In metastatic colorectal cancer (mCRC), RAS mutations drive resistance to anti-epidermal growth factor receptor antibodies. It is unclear whether RAS mutations ever become clonally undetectable. METHODS: CO.26 was a phase II clinical trial that assessed durvalumab + tremelimumab in heavily pretreated mCRC. RAS mutation status was tracked over time using circulating tumor DNA (ctDNA) sequencing at baseline, week 8, and on progression. RESULTS: Among the 95 patients with KRAS/NRAS mutations in their archival tumor tissue, 6.3% (6/95) had undetectable RAS mutations in ctDNA collected at baseline or week 8 of the CO.26 study. Of these, 67% (4/6) of disappearances were transient, with the same mutation reappearing with progressive disease. In three cases, the simultaneous persistence of other preexisting CRC-associated truncal mutations could not be demonstrated, suggestive of low tumor shedding of ctDNA, leaving the incidence of true clonal reversion to RAS-wildtype (WT) possibly as low as 3.2% (3/95). Fewer patients in the neo-RAS-WT group (33%) had greater than four lesions at trial baseline compared with patients with persistent RAS mutations (75%), P = .046. The likelihood of synchronous metastases at cancer diagnosis (33% v 63%; P = .15) or liver metastases at trial baseline (50% v 68.5%; P = .17) was not significantly different between patients with disappearing versus persistent RAS mutations. Overall survival from stage IV diagnosis (hazard ratio, 0.77 [95% CI, 0.35 to 1.72]; P = .52) was not significantly different between those with disappearing versus persistent RAS mutations. The disappearance of RAS mutations was not associated with primary tumor sidedness (P = .41), archival BRAF/MEK/ERK-mutant status (P = .16/1.00/.09), nor baseline ctDNA HER2 amplifications (P = 1.00). CONCLUSION: We identified a 3.2%-6.3% prevalence of the neo-RAS-WT phenomenon in the CO.26 trial. However, 67% of apparent cases were transient with subsequent re-emergence.

Reflective journals of students taking a positive youth-development course in a university context in Hong Kong.

To promote the holistic development of university students, a course entitled "Tomorrow's Leaders" was developed and offered at The Hong Kong Polytechnic University. Based on a case study approach, reflective journals of five outstanding students of the course are presented and analyzed (i.e., thick description), with several themes emerging from the reflection. First, the students liked the course, and they identified many positive attributes. Second, the students appreciated the instructors. Third, the students viewed that the course contributed to different aspects of their development. Fourth, some areas of improvements were proposed. In conjunction with other evaluation mechanisms, the present findings strongly suggest that the course is able to promote psychosocial competencies in university students taking this course.

Emotional competence as a positive youth development construct: a conceptual review.

The concept of emotional competence as a positive youth development construct is reviewed in this paper. Differences between emotional intelligence and emotional competence are discussed and an operational definition is adopted. Assessment methods of emotional competence with an emphasis on its quantitative nature are introduced. In the discussion of theories of emotional competence, the functionalist and developmental perspectives and the relationships with positive youth development are highlighted. Possible antecedents, especially the influence of early child-caregiver, and expected outcomes of emotional competence are examined. Practical ways to promote emotional competence among adolescents, particularly the role of parents and teachers, and the future direction of research are also discussed.

From experienced to novice: a reflective account on the changing role of front-line implementer to program trainer in Project P.A.T.H.S.

Although training plays an important role in the successful implementation of positive youth development programs, research on training and trainers in this field is grossly neglected. In this paper, a trainer of a positive youth development program in Hong Kong (Project P.A.T.H.S.; Positive Adolescent Training through Holistic Social Programmes) reflected about her transition from the role of a teacher (and program implementer) to the role of a trainer. Based on the reflection, the transformations involved, including self-perception, teaching role and teaching strategies, were highlighted. The issue of how previous experience influenced training in the context of positive youth development was also discussed. It is suggested that involvement of front-line practitioners in the training of positive youth development programs is workable, although systematic training for the novice trainers may be needed.

The role of program, people, process, policy and place (5Ps) in the implementation of a positive youth development program.

There is scant literature about identifying factors contributing to the success of the implementation of programs to help understand the interrelationships among multiple facets of implementation. In this paper, a front-line implementer reviewed the execution practice of Project P.A.T.H.S. (Positive Adolescent Training through Holistic Social Programmes) in her former school in terms of program, people, process, policy and place (5Ps). By examining the factors contributing to the success of the implementation, the authors intend to fill the gap between the research and the practical school-based front-line implementation. Although the program implementation process was examined in researchers' "expert" perspective, it would be helpful if more research employed front-line workers as collaborators and participants in the implementation process to understand what actually happen in the program implementation process.

Quantitative evaluation of the revised training program Project P.A.T.H.S. in Hong Kong.

In the extension phase of Project P.A.T.H.S. (Positive Adolescent Training through Holistic Social Programmes) in Hong Kong, potential implementers received 20 h of training (7 h of e-learning and 13 h of interactive training). Subjective outcome evaluation was conducted to evaluate the training workshops conducted in the first year of the extension phase based on the responses of 812 participants. The subjective outcome evaluation form was found to be internally consistent. Percentage findings showed that the respondents had favorable perceptions of the training program including its content, trainers, participants themselves and arrangements. The participants also felt that they had acquired knowledge, positive attitudes and skills related to the implementation of the program. The findings showed that the revised training program was effective in helping the participants to acquire the necessary knowledge, attitudes, and skills in the implementation of the program.

"Use of self" as a strategy in teaching the P.A.T.H.S. curriculum.

The purpose of promoting "use of self" or "self-disclosures" as a teaching strategy in teaching the P.A.T.H.S. curriculum is to create an interactive environment between teachers and students which can enhance the interactions between both parties. This article focuses on three major consequences of utilizing self-disclosures in the education settings, including humanizing the classroom, encouraging students' openness, and promoting teachers' awareness and reflective practice. Positive feedback of the participants of the Secondary 3 P.A.T.H.S. training programs show that participants were moved by the training instructors, who demonstrated the power of "use of self" in a humanistic manner. To retain a humanized and open classroom atmosphere depends greatly on the relational exchanges between teachers and students. This revelation should be purposeful and intentional, with appropriate boundaries and frequencies. Acknowledging the issues to consider in using "use of self" as a teaching strategy, teachers should focus attention on the process of connecting students with them. Guidelines for worker's self-disclosure are also discussed.

Ang2 inhibitors and Tie2 activators: potential therapeutics in perioperative treatment of early stage cancer.

Anti-angiogenic drugs targeting the VEGF pathway are most effective in advanced metastatic disease settings of certain types of cancers, whereas they have been unsuccessful as adjuvant therapies of micrometastatic disease in numerous phase III trials involving early-stage (resectable) cancers. Newer investigational anti-angiogenic drugs have been designed to inhibit the Angiopoietin (Ang)-Tie pathway. Acting through Tie2 receptors, the Ang1 ligand is a gatekeeper of endothelial quiescence. Ang2 is a dynamically expressed pro-angiogenic destabilizer of endothelium, and its upregulation is associated with poor prognosis in cancer. Besides using Ang2 blockers as inhibitors of tumor angiogenesis, little attention has been paid to their use as stabilizers of blood vessels to suppress tumor cell extravasation and metastasis. In clinical trials, Ang2 blockers have shown limited efficacy in advanced metastatic disease settings. This review summarizes preclinical evidence suggesting the potential utility of Ang2 inhibitors or Tie2 activators as neoadjuvant or adjuvant therapies in the prevention or treatment of early-stage micrometastatic disease. We further discuss the rationale and potential of combining these strategies with immunotherapy, including immune checkpoint targeting antibodies.

An Intervention to Improve Chlamydia and Gonorrhea Testing Among Adolescents in Primary Care.

BACKGROUND AND OBJECTIVES: Rates of chlamydia and gonorrhea among adolescents continue to rise. We aimed to evaluate if a universal testing program for chlamydia and gonorrhea improved testing rates in an urban general pediatric clinic and an urban family medicine clinic within a system of federally qualified health care centers and evaluated the feasibility, cost, and logistic challenges of expanding implementation across 28 primary care clinics within a federally qualified health care centers system. METHODS: A universal testing quality improvement program for male and female patient 14 to 18 years old was implemented in a general pediatrics and family medicine clinic in Denver, Colorado. The intervention was evaluated by using a controlled pre-post quasi-experimental design. The difference in testing rates due to the intervention was assessed by using a difference-in-differences regression model weighted with the inverse probability of treatment. RESULTS: In total, 15 541 pediatric encounters and 5420 family medicine encounters were included in the analyses. In pediatrics, the unadjusted testing rates increased from 32.0% to 66.7% in the intervention group and from 20.9% to 28.9% in the comparison group. For family medicine, the rates increased from 38.5% to 49.9% in the intervention group and decreased from 26.3% to 24.8% in the comparison group. The intervention resulted in an adjusted increase in screening rates of 25.2% (P < .01) in pediatrics and 11.8% (P < .01) in family medicine. The intervention was well received and cost neutral to the clinic. CONCLUSIONS: Universal testing for chlamydia and gonorrhea in primary care pediatrics and family medicine is a feasible approach to improving testing rates .

A systems biology perspective on sVEGFR1: its biological function, pathogenic role and therapeutic use.

Angiogenesis is the growth of new capillaries from pre-existent microvasculature. A wide range of pathological conditions, from atherosclerosis to cancer, can be attributed to either excessive or deficient angiogenesis. Central to the physiological regulation of angiogenesis is the vascular endothelial growth factor (VEGF) system--its ligands and receptors (VEGFRs) are thus prime molecular targets of pro-angiogenic and anti-angiogenic therapies. Of growing interest as a prognostic marker and therapeutic target in angiogenesis-dependent diseases is soluble VEGF receptor-1 (sVEGFR1, also known as sFlt-1)--a truncated version of the cell membrane-spanning VEGFR1. For instance, it is known that sVEGFR1 is involved in the endothelial dysfunction characterizing the pregnancy disorder of pre-eclampsia, and sVEGFR1's therapeutic potential as an anti-angiogenic agent is being evaluated in pre-clinical models of cancer. This mini review begins with an examination of the protein domain structure and biomolecular interactions of sVEGFR1 in relation to the full-length VEGFR1. A synopsis of known and inferred physiological and pathological roles of sVEGFR1 is then given, with emphasis on the utility of computational systems biology models in deciphering the molecular mechanisms by which sVEGFR1's purported biological functions occur. Finally, we present the need for a systems biology perspective in interpreting circulating VEGF and sVEGFR1 concentrations as surrogate markers of angiogenic status in angiogenesis-dependent diseases.

VEGF and soluble VEGF receptor-1 (sFlt-1) distributions in peripheral arterial disease: an in silico model.

Vascular endothelial growth factor (VEGF) is a key regulator of angiogenesis, the growth of new capillaries from existing microvasculature. In peripheral arterial disease (PAD), lower extremity muscle ischemia develops downstream of atherosclerotic obstruction. A working hypothesis proposed that the maladaptive overexpression of soluble VEGF receptor 1 (sVEGFR1) in ischemic muscle tissues, and its subsequent antagonism of VEGF bioactivity, may contribute to the deficient angiogenic response in PAD, as well as the limited success of therapeutic angiogenesis strategies where exogenous VEGF genes/proteins are delivered. The objectives of this study were to develop a computational framework for simulating the systemic distributions of VEGF and sVEGFR1 (e.g., intramuscular vs. circulating, free vs. complexed) as observed in human PAD patients and to serve as a platform for the systematic optimization of diagnostic tools and therapeutic strategies. A three-compartment model was constructed, dividing the human body into the ischemic calf muscle, blood, and the rest of the body, connected through macromolecular biotransport processes. Detailed molecular interactions between VEGF, sVEGFR1, endothelial surface receptors (VEGFR1, VEGFR2, NRP1), and interstitial matrix sites were modeled. Our simulation results did not support a simultaneous decrease in plasma sVEGFR1 during PAD-associated elevations in plasma VEGF reported in literature. Furthermore, despite the overexpression in sVEGFR1, our PAD control demonstrated increased proangiogenic signaling complex formation, relative to our previous healthy control, due to sizeable upregulations in VEGFR2 and VEGF expression, thus leaving open the possibility that impaired angiogenesis in PAD may be rooted in signaling pathway disruptions downstream of ligand-receptor binding.

The presence of VEGF receptors on the luminal surface of endothelial cells affects VEGF distribution and VEGF signaling.

Vascular endothelial growth factor (VEGF) is a potent cytokine that binds to specific receptors on the endothelial cells lining blood vessels. The signaling cascade triggered eventually leads to the formation of new capillaries, a process called angiogenesis. Distributions of VEGF receptors and VEGF ligands are therefore crucial determinants of angiogenic events and, to our knowledge, no quantification of abluminal vs. luminal receptors has been performed. We formulate a molecular-based compartment model to investigate the VEGF distribution in blood and tissue in humans and show that such quantification would lead to new insights on angiogenesis and VEGF-dependent diseases. Our multiscale model includes two major isoforms of VEGF (VEGF(121) and VEGF(165)), as well as their receptors (VEGFR1 and VEGFR2) and the non-signaling co-receptor neuropilin-1 (NRP1). VEGF can be transported between tissue and blood via transendothelial permeability and the lymphatics. VEGF receptors are located on both the luminal and abluminal sides of the endothelial cells. In this study, we analyze the effects of the VEGF receptor localization on the endothelial cells as well as of the lymphatic transport. We show that the VEGF distribution is affected by the luminal receptor density. We predict that the receptor signaling occurs mostly on the abluminal endothelial surface, assuming that VEGF is secreted by parenchymal cells. However, for a low abluminal but high luminal receptor density, VEGF binds predominantly to VEGFR1 on the abluminal surface and VEGFR2 on the luminal surface. Such findings would be pertinent to pathological conditions and therapies related to VEGF receptor imbalance and overexpression on the endothelial cells and will hopefully encourage experimental receptor quantification for both luminal and abluminal surfaces on endothelial cells.

Computational kinetic model of VEGF trapping by soluble VEGF receptor-1: effects of transendothelial and lymphatic macromolecular transport.

Vascular endothelial growth factor (VEGF) signal transduction through the cell surface receptors VEGFR1 and VEGFR2 regulates angiogenesis-the growth of new capillaries from preexistent microvasculature. Soluble VEGF receptor-1 (sVEGFR1), a nonsignaling truncated variant of VEGFR1, has been postulated to inhibit angiogenic signaling via direct sequestration of VEGF ligands or dominant-negative heterodimerization with surface VEGFRs. The relative contributions of these two mechanisms to sVEGFR1's purported antiangiogenic effects in vivo are currently unknown. We previously developed a computational model for predicting the compartmental distributions of VEGF and sVEGFR1 throughout the healthy human body by simulating the molecular interaction networks of the VEGF ligand-receptor system as well as intercompartmental macromolecular biotransport processes. In this study, we decipher the dynamic processes that led to our prior prediction that sVEGFR1, through its ligand trapping mechanism alone, does not demonstrate significant steady-state antiangiogenic effects. We show that sVEGFR1-facilitated tissue-to-blood shuttling of VEGF accounts for a counterintuitive and drastic elevation in plasma free VEGF concentrations after both intramuscular and intravascular sVEGFR1 infusion. While increasing intramuscular VEGF production reduces free sVEGFR1 levels through increased VEGF-sVEGFR1 complex formation, we demonstrate a competing and opposite effect in which increased VEGF occupancy of neuropilin-1 (NRP1) and the corresponding reduction in NRP1 availability for internalization of sVEGFR1 unexpectedly increases free sVEGFR1 levels. In conclusion, dynamic intercompartmental transport processes give rise to our surprising prediction that VEGF trapping alone does not account for sVEGFR1's antiangiogenic potential. sVEGFR1's interactions with cell surface receptors such as NRP1 are also expected to affect its molecular interplay with VEGF.

The Social Indicators Movement: Progress, Paradigms, Puzzles, Promise and Potential Research Directions.

This paper is a response to the article entitled "Fifty years after the Social Indicators Movement: Has the promise been fulfilled?" by Ken Land and Alex Michalos (2015) which constitutes a careful review of the historical development of the Social Indicators Movement, utility of social indicators in shaping the concept of quality of life and subjective well-being, and issues deserving social indicators research in future. In this response paper, we join in the discussion by highlighting five issues-progress, paradigms, puzzles, promise, and potential research directions of social indicators research. In terms of progress, while we have accomplished many tasks proposed by Solomon et al. (The quality of life, Sage, London 1980), some of them are yet to be achieved. Regarding research paradigms surrounding social indicators, researchers have primarily used positivistic or post-positivistic orientation to conduct and interpret social indicators research, with relatively fewer studies using interpretive, constructionist or critical theory perspective. There are also several puzzles deserving consideration. These include (a) the use of "other types of evidence", particularly qualitative data; (b) evaluation of social programs; (c) feasibility of assessing "social progress"; (d) choice of social indicators; (e) interpretation of findings; (f) methodological debates; and (g) explanations for social change. Finally, the promise of social indicators research to promote quality of life and potential future research directions of social indicators research are discussed.