Continental Philosophy

Piper's question and ours: a role for adversity in group-centred views of non-agentive shame Abstract This paper aims to contribute to 'group-centred views' of non-agentive shame (victim shame, oppression shame), by linking them to an 'anepistemic' model of the experience and impact of human failing. One of the most vexing aspects of those group-centred views remains how susceptivity to such shame ought to be understood. This contribution focuses on how a basic familiarity with adversity, in everyday life, may open individuals up to these forms of shame. If, per group-centred views, non-agentive shame is importantly driven by participation in social practices with others, a better understanding of the impact of adversity on individuals' lives may offer a way of explaining how embodied experience instils in individuals a need for such participation. The upshot is an understanding of the individual's susceptivity to non-agentive shame, which affords it the same legitimacy as more conventional notions of shame.

Motor intentionality and the intentionality of improvisation: a contribution to a phenomenology of musical improvisation Abstract The intentionality of improvisation represents surely one of the most pressing and controversial issues in contemporary action theory: how do we find the way to characterize the proper intentionality of improvisation, which is an unplanned yet intentional action? This article will address this question bringing together Merleau-Ponty's motor intentionality and Bergson's conception of duration. My argument will unfold in three main stages. First, I will briefly describe the traditional scheme that is used to think of intentional action in contemporary action theory and discuss how the phenomenon of improvisation casts doubts on it. Second, I will outline an initial, and provisional account of improvisation by crossing the descriptions of musical improvisation provided by Jankélévitch with the testimonials of two improvisatory composers—Enrico Pieranunzi and Keith Jarrett—and reports from Charles Rosen, an American pianist and Roger Sessions, an American composer. Finally, I will refine the basic concepts and lay out a phenomenological account of improvisation, by extending and applying the phenomenological notion of motor intentionality to the examples and testimonials gathered from the observation of a specific kind of improvisatory activity—musical composition. This methodology is intended to contrast both with more standard philosophical approaches based on hypothetical examples, and with more standard laboratory-based methodologies in cognitive sciences, psychology, and experimental philosophy. Overall, this approach is intended to redress the balance of action theory—one-sided directed towards planning, as a key aspect of human agency—with an analysis of the bodily and responsive aspect of intentionality.

Sensibility and the otherness of the world: Levinas and Merleau-Ponty Abstract Sensibility has traditionally been defined as a relation with the world's exteriority. However, a certain post-husserlian phenomenology tends to reverse this definition and to redefine sensibility as an internal relation that takes place from within the world. This article focuses on this phenomenological concept of "sensibility" in Levinas and Merleau-Ponty and intends to show that this concept rests upon the presupposition of an alternative according to which we would have whether a sensible experience of identity, or an acosmic experience of otherness—whether a wordly experience of the same or a worldless experience of otherness. Yet, by reducing sensibility to the experience of the world's interiority and rejecting otherness beyond any worldly experience, this conception fails to account for a significant dimension of sensibility—namely, sensibility as the experience of the world's own otherness, foreignness or exteriority. It is our hope that, from the critical exposition of this alternative, will eventually appear in conclusion the significant part of this forgotten dimension of sensibility.

Kinesthesia: An extended critical overview and a beginning phenomenology of learning Abstract This paper takes five different perspectives on kinesthesia, beginning with its evolution across animate life and its biological distinction from, and relationship to proprioception. It proceeds to document the historical derivation of "the muscle sense," showing in the process how analytic philosophers bypass the import of kinesthesia by way of "enaction," for example, and by redefinitions of "tactical deception." The article then gives prominence to a further occlusion of kinesthesia and its subduction by proprioception, these practices being those of well-known phenomenologists, practices that exemplify an adultist perspective supported in large part by the writings of Merleau-Ponty. Following this extended critical review, the article shows how Husserl's phenomenology enlightens us about kinesthesia and in doing so offers us substantive clues to the phenomenology of learning as it takes place in the development and acquisition of skillful movement. It shows further how phenomenological methodology contrasts markedly with existential analysis, most significantly in its recognition of, and its ability to set forth a developmental history, a veritable genetic phenomenology that is basically a phenomenology of learning anchored in kinesthesia. After showing how that phenomenology of learning finds mutual validation in a classic empirical study of infant movement, the article ends by highlighting how human "I cans" are grounded in "I move," specifically, in the pan-human ability to learn one's body and learn to move oneself.

From existential alterity to ethical reciprocity: Beauvoir's alternative to Levinas Abstract While Simone de Beauvoir's theory of alterity has been the topic of much discussion within Beauvoir scholarship, feminist theory, and social and political philosophy, it has not commonly been a reference point for those working within ethics. However, Beauvoir develops a novel view that those concerned with the ethical import of respect for others should consider seriously, especially those working within the Levinasian tradition. I claim that Beauvoir distinguishes between two forms of otherness: namely, existential alterity and sociopolitical alterity. While sociopolitical alterity is a contingent and surmountable form of otherness that results from oppression of individuals and groups, existential alterity is a necessary feature of the human condition that discloses the foreignness of the other as a freedom. Out of this view of existential alterity, I argue, Beauvoir develops an ethic of asymmetrical reciprocity. In contrast with Levinas, who dismisses reciprocity as a symmetrical or reversible model of relation that minimizes difference, Beauvoir promulgates a view of reciprocity that does not fall into the problems that Levinas diagnoses. Moreover, asymmetrical reciprocity more successfully figures the ethical relation to the other than the absolute asymmetry one finds in Levinas, which becomes evident through revisiting Levinas's account of eros and contrasting it with that of Beauvoir.

Forgiveness as institution: a Merleau-Pontian account Abstract Recent literature on forgiveness suggests that a successful account of the phenomenon must satisfy at least three conditions: it must be able to explain how forgiveness can be articulate, uncompromising, and elective. These three conditions are not logically inconsistent, but the history of reflection on the ethics of forgiveness nonetheless suggests that they are in tension. Accounts that emphasize articulateness and uncompromisingness tend to suggest an excessively deflationary understanding of electiveness, underestimating the degree to which forgiveness is a gift. Accounts that emphasize electiveness, on the other hand, tend to weaken the safeguards that keep forgiveness distinct from condonation, excuse, or mere servility. I argue in this paper that we can do justice to the three conditions by understanding forgiveness in terms of the concept of institution that Maurice Merleau-Ponty developed in his work from the early- to mid-1950s.

The relevance of the theory of pseudo-culture Abstract Some 60 years separate us from Theodor W. Adorno's "Theory of pseudo-culture." Yet Adorno's analysis might never have been as pertinent and as compelling as it is in the present moment. The dawn of the "post-truth" era, and the persistent impact of the culture industry on human sensibility and capacity for critical self-reflection, call for a return to Adorno's critical theorisation of pseudo-culture. This paper revisits Adorno's assessment of pseudo-culture and proposes a reconstruction of some of his most compelling arguments on the subject in light of the present socio-historical circumstances. The paper starts with a concise discussion of the notions of Kultur, Bildung and Halbbildung in relation to Adorno's thought. It then discusses the effects of pseudo-culture on human experience by looking into the role of opinions—in particular, what Adorno terms "delusional" opinions—in contemporary late capitalist reality. Finally, the paper ends with a juxtaposition of the barbarism of the banal and neoteric barbarism. I argue that, whereas the former stuns culture and impels it to regress to a state of pseudo-culture, the latter gives it new impetus by opening up new theoretical and practical paths.

Attitudes and illusions: Herbert Leyendecker's phenomenology of perception Abstract In this paper, I discuss aspects of Herbert Leyendecker's 1913 doctoral dissertation, Towards the Phenomenology of Deceptions (Zur Phänomenologie der Täuschungen), which he defended in 1913 at the University of Munich. Leyendecker was a member of the Munich and Göttingen Phenomenological Circles. In my discussion of his largely neglected views, I explore the connection between his ideas concerning "attitudes" (Einstellungen), e.g., of searching for, observing, counting, or working with objects, and the central topic of his text, perceptual illusions, thematized by Leyendecker as a kind of perceptual "deception" (Täuschung). Indeed, Leyendecker argues that a change of attitude is a necessary aspect of an illusion. I argue that Leyendecker's use of the notion of attitude in accounting for illusions is problematic; yet I also suggest that his ideas are not devoid of philosophical interest, in relation to current debates.

Personal identity and the otherness of one's own body Abstract Locke claims that a person's identity over time consists in the unity of consciousness, not in the sameness of the body. Similarly, the phenomenological approach refuses to see the criteria of identity as residing in some externally observable bodily features. Nevertheless, it does not accept the idea that personal identity has to consist either in consciousness or in the body. We are self-aware as bodily beings. After providing a brief reassessment of Locke and the post-Lockean discussion, the article draws on phenomenological arguments that show the body as lived, that is, lived as one's own body, but also possibly as "other" or "strange." Against what has been claimed in recent writing, especially in literature on Merleau-Ponty, the author argues that the "mineness" of the body and its "alterity" are not two mutually exclusive features. In the final part of the article, the author suggests that the becoming strange of one's own body may legitimately be considered as a prominent experience of what it means to be a person.

Geoffrey Dierckxsens: Paul Ricoeur's moral anthropology—singularity, responsibility, and justice

Value Inquiry

Iddo Landau, Finding Meaning in an Imperfect World. Oxford, England: Oxford University Press, 2017. ISBN 9780190657666, $25, Hbk

Review of Bryan Caplan's The Case Against Education

Mackie's Conceptual Reform Moral Error Theory

Is Monogamy Morally Permissible?

Daoist Metaethics

Kant's Phenomenology of Humiliation Abstract This paper presents a new reading of Kant's moral feeling: in lieu of highlighting a positive feeling of respect, I am interested in a thorough phenomenological interpretation of a negative feeling of humiliation. The paper's tone is set by underscoring that human moral Gesinnung is that which is necessarily cultivated, which entails that the striving moral agent, among other things, learns to identify and confront inclinations. It is argued, then, that one's mindfulness of the various kinds of pain of humiliated inclinations presupposes the agent's aesthetic attunement to the law of duty. To this end, two phenomenological interpretations are offered. First, general humiliation Kant caters for in the Critique of Practical Reason. Second, specific humiliation Kant alludes to in the Metaphysics of Morals. On the whole, the paper's findings ascertain the epistemic weight of humiliation, which to date has been undervalued.

Fighting Pleasure: Plato and the Expansive View of Courage

From Factitious to Veridical Attribution of Virtue: How Wang Yangming Can Do a Better Job than Alfano in Facilitating Virtue Acquisition

Constructivism and the Problem of Normative Indeterminacy

Christopher Freiman, Unequivocal Justice. New York, Routledge, 2017. ISBN 9-781-13862822-9, $140, Hbk

Supportive Care

Medication-related osteonecrosis of the jaw incidence in patients exposed concomitantly to bone resorption inhibitors and vascular endothelial growth factor receptor tyrosine kinase inhibitors: is it generalizable to all solid tumors?

Factors influencing magnesium infusions in hematopoietic cell transplants

A review of the Rapid Response Radiotherapy Program in patients with advanced cancer referred for palliative radiotherapy over two decades Abstract Introduction The Rapid Response Radiotherapy Program (RRRP) is an outpatient radiotherapy clinic for palliative cancer patients where consultation, planning, and radiation treatment can take place in 1 day, allowing for rapid access to care. The objective of this study was to compare the patient population and overall survival of patients seen in the RRRP from 2014 to 2017 to that of patients seen in 1999. Method Patient characteristics including sex, primary cancer site, sites of metastases, and Karnofsky Performance Status (KPS) were recorded at each clinic visit. Date of death (DOD) was retrieved from the Patient Care System (PCS) and Excelicare. To show overall survival from the first clinic visit, a Kaplan-Meier overall survival curve was generated in all patients from 2014 to 2017. Results Five hundred ninety-six patients were included in the final analysis. Most patients were male (n = 347) with a primary cancer site of the lung (n = 165) and metastases to the bone (n = 475). Actuarial median overall survival was 15.3 months. In 1999, 395 patients were analyzed, in which a primary of the lung (n = 143) and metastases to the bone (n = 277) were the most prevalent. An additional 72 patients in this population had brain metastases. The actuarial median survival of the 1999 population was 4.5 months. Conclusion The changing patient population in the RRRP has resulted in visible changes in survival. This may reflect differences in the proportion of patients with specific primaries and sites of metastases, as well as improvements in the availability of palliative radiation over the last two decades.

Moving Cancer Care Ontario's Exercise for People with Cancer guidelines into oncology practice: using the Theoretical Domains Framework to validate a questionnaire Abstract Evidence supporting the benefits of exercise surrounding cancer treatment has led to internationally published guidelines, with minimal uptake by oncology care providers (OCPs). There is a need to understand how to implement research evidence into practice. Our team developed a questionnaire to assess OCPs' knowledge of exercise guidelines and barriers/facilitators to exercise counseling and program referral. We validated the questionnaire using the Theoretical Domains Framework, a knowledge translation (KT) framework used to implement evidence-based guidelines into practice. In this commentary, we describe this process and the rationale for integrating a KT framework into intervention development and implementation in oncology practice. The revised questionnaire, entitled Clinicians Perspectives on Exercise in Patients with Cancer (CliPEC), is shared to facilitate the implementation process and allow for comparison across oncology practices.

Cancer survivorship care plans, financial toxicity, and financial planning alleviating financial distress among cancer survivors Abstract Concomitant with the increasing use of cancer care plans has been an increasing awareness of the potential for oncology care to result in long-term financial burdens and financial toxicity. Cancer survivors can benefit from information on support and resources to help them navigate the challenges after acute cancer treatment. While cancer survivorship plans could be a vehicle for patients to receive information on how to mitigate financial toxicity, cancer survivorship plans have typically not dealt with the financial impact of cancer treatment or follow-up care. Embedding information into cancer survivorship plans on how to reduce or avoid financial toxicity presents an opportunity to address a highly prevalent patient need. Patient-centered qualitative studies are needed to assess the type, format, and level of detail of the information provided.

A systematic review of psychological interventions for patients with head and neck cancer Abstract Aim The purpose of this systematic review is to identify psychological interventions that have been effective at improving quality of life and reducing psychological distress (depression and anxiety) in patients with head and neck cancer. Methods All relevant peer-reviewed articles published between March 1980 and March 2017 were identified through an electronic search of five databases: Medline, Embase, PsycINFO, Scopus, and Academic Search Complete. Risk of bias was independently assessed by two reviewers using the Crowe Critical Appraisal Tool (CCAT). Following this, a narrative synthesis of the findings was completed. Results Twenty-one unique intervention studies were identified. Interventions tested included cognitive behavioural therapy (CBT), psychoeducation, meditation/mindfulness, group therapy, and telehealth initiatives. Ten studies utilised a randomised controlled design. Five of these investigated CBT and three examined psychoeducation, with the greatest empirical support found for these intervention types. However, the majority of studies were underpowered to detect significant effects and did not examine whether improvements in quality of life and psychological well-being were sustained over time. Conclusions Further research is needed to investigate the effects of psychological interventions among patients with head and neck cancer, using randomised controlled designs, adequately powered samples, and long-term follow-up. This would allow evidence-based recommendations to be made regarding the most appropriate interventions to implement in clinical practice. Trial registration CRD42017069851

The efficacy of oral piroxicam fast-dissolving tablets versus sublingual fentanyl in incident breakthrough pain due to bone metastases: a double-blinded randomized study Abstract Purpose Breakthrough pain (BTP) is a transient exacerbation of pain occurring in a patient with chronic, persistent pain. The most common type is incident pain that is mostly related to bone metastases. The oral mucosa is an attractive route for drug delivery. Sublingual fentanyl preparations are a very attractive agent in controlling attacks of BTP due to its rapid absorption through the oral mucosa. Non-steroidal anti-inflammatory drugs (NSAIDs) play a key role as a first step in treatment of cancer pain; piroxicam sublingual formulations could be a useful alternative in controlling incident pain. Our study hypothesis is to evaluate the efficacy of sublingual fentanyl versus oral piroxicam fast-dissolving tablets in patients with incident pain and its impact on functional status. Patients and methods A cohort of 100 adults of both genders suffering from bone metastases. Patients were assigned to receive either sublingual fentanyl tablet (group 1) or oral piroxicam fast-dissolving tablets (group 2). The pain intensity reduction on a 0–10 visual analog scale (VAS), frequency of BTP attacks, and onset of pain relief. Secondary end points included the functional interference items of the Brief Pain Inventory (BPI). Results There is no significant difference between the two groups regarding the patients' demographics. Significant decline of the VAS in each group in comparison to the pretreatment values (p = 0.001). Non-significant changes of the VAS, duration of pain attacks, and number of rescue doses in comparing both groups were measured. There was significant reduction in group 2 BPI regarding the relation with others, sleep pattern and enjoyment of life parameters at 2 and 4 weeks (p = 0.001). Conclusion Our study demonstrated that oral piroxicam fast-dissolving tablet is an analgesic alternative to sublingual fentanyl in patients with bone metastasis to control incidental BTP attacks with more favorable cost-benefit values.

Trajectory of insomnia symptoms in older adults with lung cancer: using mixed methods Abstract Context A knowledge gap exists in our understanding of the illness and insomnia symptom treatment trajectory in adults with inoperable non-small cell lung cancer (NSCLC). Objectives Compare valid and reliable sleep-wake measures for insomnia to interpretations of narrative descriptions of sleep to improve our comprehension of sleep-wake disturbances in adults with NSCLC. Methods This study employed mixed methods (quantitative and qualitative) in a longitudinal design to study adults (n = 26) from ambulatory thoracic clinics. Valid and reliable surveys (Pittsburgh Sleep Quality Index, Epworth Sleepiness Scale), 7-day sleep diary, and actigraphy were obtained with interview narrative interpretations of sleep experiences in the context of lung cancer. Data collection occurred at four-time points: baseline (before chemotherapy), pre-second chemotherapy, pre-third chemotherapy, and 6 months from baseline. Sleep measures were compared to interpretations from interview narratives to understand context of survey measures. Results Objective quantitative results were congruent with interview narrative interpretations that reflected participants' sleep-wake experiences. Objective sleep-wake measures for insomnia over-time described increasing sleep latency and decreasing sleep duration. The interview narratives provided context and insight into participants' subjective insomnia experiences. While participants' insomnia symptoms were present, they were resigned to endure insomnia, and the subjective measures reflected a more positive perception of sleep outcomes. Conclusion A mixed methods approach provides a deeper understanding of sleep-wake disturbances and the differing quantitative objective and subjective results of sleep measures in the context of the participants' experience of the trajectory of insomnia symptoms before, during, and after lung cancer treatment.

Understanding patient choices regarding breast reconstruction after mastectomy for breast cancer Abstract Purpose In Australia, about 40% of patients undergo mastectomy to treat breast cancer, with negative impacts on body image, sexual function and quality of life. Whilst breast reconstruction is associated with increased patient self-esteem and a greater sense of wholeness and well-being, the national reconstruction rate is low at 18%. This study aimed to compare demographics, treatment factors and information provision about breast reconstruction in women who had and did not have breast reconstruction following mastectomy treatment and identify goals and concerns underpinning women's reconstruction decisions. Methods Female patients who had a mastectomy to treat breast cancer between 2010 and 2014 in a culturally and linguistically diverse (CALD) and socially disadvantaged region participated in a cross-sectional study, completing a questionnaire in their language of choice (English, Vietnamese, Chinese or Arabic). Results Completed surveys were returned by 168 women (42% response rate; 77% English-speaking), of whom only 19.0% (n = 32) reported having had breast reconstruction. Reconstruction rates were significantly lower in women who reported speaking a language other than English at home versus only English (37.5% vs 62.5%, p = 0.03). However, all women expressed a desire for more information about breast reconstruction and more support to make their decision about breast reconstruction. Conclusions Patients identified a need for greater information provision on breast reconstruction, highlighting an urgent need for resources specifically about breast reconstruction, particularly for non-English-speaking patients. Greater provision of information prior to mastectomy is critical to underpin breast cancer patients' decisions about breast reconstruction, especially for non-English speaking patients.

Joint pain and falls among women with breast cancer on aromatase inhibitors Abstract Purpose Arthralgia is common among women with breast cancer on adjuvant aromatase inhibitor (AI) therapy. Pain is associated with falls in the general population; however, little is known about the relationship between arthralgia and falls among AI users. Our objective was to determine whether joint pain severity and interference predict future falls. Methods We conducted a prospective cohort study of postmenopausal women with stage I-III estrogen receptor-positive breast cancer who were prescribed a third-generation AI. Arthralgia symptoms were measured at baseline using a modified version of the Brief Pain Inventory. Fall occurrence was obtained at 24-month follow-up. Results Among 667 participants (median age 63 years, interquartile range 57–69 years), 232 (35%, 95% CI 31 to 39%) reported falls 12–24 months after baseline. Among women who fell, 65 (28%) reported seeking medical assistance. After controlling for multiple fall risk factors, we found significant non-linear associations between baseline joint pain severity and risk of falls (p = 0.001). Women with joint pain severity scores ≥ 4 had a more than twofold increase in fall risk compared to those without pain (41% vs. 20%). We observed a similar relationship for pain interference and fall risk (p < 0.001). Fewer than half of participants reported having been asked about falls in the past 12 months by their primary care physician (44%) or oncologist (36%). Conclusion Joint pain increases the risk of falls among women with breast cancer on adjuvant AI therapy. Health care providers should evaluate and manage arthralgia symptoms and implement fall-prevention strategies for those who are at increased risk.

Natural Medicines

Quantification of Panax notoginseng saponins metabolites in rat plasma with in vivo gut microbiota-mediated biotransformation by HPLC-MS/MS Publication date: March 2019 Source: Chinese Journal of Natural Medicines, Volume 17, Issue 3 Author(s): Yin-Ping GUO, Man-Yun CHEN, Li SHAO, Wei ZHANG, Tai RAO, Hong-Hao ZHOU, Wei-Hua HUANG Abstract Panax notoginseng saponins (PNS) are the major components of Panax notoginseng, with multiple pharmacological activities but poor oral bioavailability. PNS could be metabolized by gut microbiota in vitro, while the exact role of gut microbiota of PNS metabolism in vivo remains poorly understood. In this study, pseudo germ-free rat models were constructed by using broad-spectrum antibiotics to validate the gut microbiota-mediated transformation of PNS in vivo. Moreover, a high performance liquid chromatography-electrospray ionization tandem mass spectrometry (HPLC-ESI-MS/MS) was developed for quantitative analysis of four metabolites of PNS, including ginsenoside F1 (GF1), ginsenoside Rh2 (GRh2), ginsenoside compound K (GCK) and protopanaxatriol (PPT). The results showed that the four metabolites could be detected in the control rat plasma, while they could not be determined in pseudo germ-free rat plasma. The results implied that PNS could not be biotransformed effectively when gut microbiota was disrupted. In conclusion, gut microbiota plays an important role in biotransformation of PNS into metabolites in vivo.

Two new nimbolinin- and trichilin-class limonoids isolated from the fruits of Melia azedarach Publication date: March 2019 Source: Chinese Journal of Natural Medicines, Volume 17, Issue 3 Author(s): Lu QIU, Li HENG, Rong XU, Jun LUO, Yi LI Abstract Two new furan fragment isomerized limonoids, meliazedalides A and B (compounds 1 and 2), were isolated from the fruits of Melia azedarach Linn.. Their chemical structures were elucidated on the basis of HR-ESI-MS and 1D and 2D NMR data, which belonged to nimbolinin- and trichilin-class, respectively. Compound 2 exhibited weak inhibitory effect on NO production in lipopolysaccharide (LPS)-activated RAW 264.7 macrophages with IC50 being 37.41 μmol·L−1.

Lower clearance of sodium tanshinone IIA sulfonate in coronary heart disease patients and the effect of total bilirubin: a population pharmacokinetics analysis Publication date: March 2019 Source: Chinese Journal of Natural Medicines, Volume 17, Issue 3 Author(s): Wei-Wei QIN, Li WANG, Zheng JIAO, Bin WANG, Cheng-Yu WANG, Li-Xuan QIAN, Wei-Lin QI, Ming-Kang ZHONG Abstract This study developed a population pharmacokinetic model for sodium tanshinone IIA sulfonate (STS) in healthy volunteers and coronary heart disease (CHD) patients in order to identify significant covariates for the pharmacokinetics of STS. Blood samples were obtained by intense sampling approach from 10 healthy volunteers and sparse sampling from 25 CHD patients, and a population pharmacokinetic analysis was performed by nonlinear mixed-effect modeling. The final model was evaluated by bootstrap and visual predictive check. A total of 230 plasma concentrations were included, 137 from healthy volunteers and 93 from CHD patients. It was a two-compartment model with first-order elimination. The typical value of the apparent clearance (CL) of STS in CHD patients with total bilirubin (TBIL) level of 10 μmol(L−1 was 48.7 L(h−1 with inter individual variability of 27.4%, whereas that in healthy volunteers with the same TBIL level was 63.1 L(h−1. Residual variability was described by a proportional error model and estimated at 5.2%. The CL of STS in CHD patients was lower than that in healthy volunteers and decreased when TBIL levels increased. The bootstrap and visual predictive check confirmed the stability and validity of the final model. These results suggested that STS dosage adjustment might be considered based on TBIL levels in CHD patients.

Two natural molecules preferentially inhibit azole-resistant Candida albicans with MDR1 hyperactivation Publication date: March 2019 Source: Chinese Journal of Natural Medicines, Volume 17, Issue 3 Author(s): Hong-Zhuo SHI, Wen-Qiang CHANG, Ming ZHANG, Hong-Xiang LOU Abstract Antifungal drug resistance is a significant clinical problem, and antifungal agents that can evade resistance are urgently needed. In infective niches, resistant organisms often co-existed with sensitive ones, or a subpopulation of antibiotic-susceptible organisms may evolve into resistant ones during antibiotic treatment and eventually dominate the whole population. In this study, we established a co-culture assay in which an azole-resistant Candida albicans strain was mixed with a susceptible strain labeled with green fluorescent protein to mimic in vivo conditions and screen for antifungal drugs. Fluconazole was used as a positive control to verify the validity of this co-culture assay. Five natural molecules exhibited antifungal activity against both susceptible and resistant C. albicans. Two of these compounds, retigeric acid B (RAB) and riccardin D (RD), preferentially inhibited C. albicans strains in which the efflux pump MDR1 was activated. This selectivity was attributed to greater intracellular accumulation of the drugs in the resistant strains. Changes in sterol and lipid compositions were observed in the resistant strains compared to the susceptible strain, and might increase cell permeability to RAB and RD. In addition, RAB and RD interfered with the sterol pathway, further aggregating the decrease in ergosterol in the sterol synthesis pathway in the MDR1-activated strains. Our findings here provide an alternative for combating resistant pathogenic fungi.

The Zuo Jin Wan Formula increases chemosensitivity of human primary gastric cancer cells by AKT mediated mitochondrial translocation of cofilin-1 Publication date: March 2019 Source: Chinese Journal of Natural Medicines, Volume 17, Issue 3 Author(s): Meng-Yao SUN, Dan-Dan WANG, Jian SUN, Xiao-Hua ZHAO, Si CAI, Qiu-Xue WU, Tao JIE, Zhen-Hua NI, Jian-Yue SUN, Qing-Feng TANG Abstract Resistance to cisplatin (DDP)-based chemotherapy is a major cause of treatment failure in human gastric cancer (GC). It is necessary to identify the drugs to re-sensitize GC cells to DDP. In our previous research, Zuo Jin Wan Formula (ZJW) has been proved could increase the mitochondrial apoptosis via cofilin-1 in a immortalized cell line, SGC-7901/DDP. Due to the immortalized cells may still difficult highly recapitulate the important molecular events in vivo, primary GC cells model derived from clinical patient was constructed in the present study to further evaluate the effect of ZJW and the underlying molecular mechanism. Immunofluorescent staining was used to indentify primary cultured human GC cells. Western blotting was carried out to detect the protein expression. Cell Counting Kit-8 (CCK-8) was used to evaluate cell proliferation. Flow cytometry analysis was performed to assess cell apoptosis. ZJW inhibited proliferation and induced apoptosis in primary DDP-resistant GC cells. Notably, the apoptosis in GC cells was mediated by inducing cofilin-1 mitochondrial translocation, down-regulating Bcl-2 and up-regulating Bax expression. Surprisingly, the level of p-AKT protein was higher in DDP-resistant GC cells than that of the DDP-sensitive GC cells, and the activation of AKT could attenuate ZJW-induced sensitivity to DDP. These data revealed that ZJW can increase the chemosensitivity in DDP-resistant primary GC cells by inducing mitochondrial apoptosis and AKT inactivation. The combining chemotherapy with ZJW may be an effective therapeutic strategy for GC chemoresistance patients.

Houttuynia cordata polysaccharide alleviated intestinal injury and modulated intestinal microbiota in H1N1 virus infected mice Publication date: March 2019 Source: Chinese Journal of Natural Medicines, Volume 17, Issue 3 Author(s): Mei-Yu CHEN, Hong LI, Xiao-Xiao LU, Li-Jun LING, Hong-Bo WENG, Wei SUN, Dao-Feng CHEN, Yun-Yi ZHANG Abstract Houttuynia cordata polysaccharide (HCP) is extracted from Houttuynia cordata, a key traditional Chinese medicine. The study was to investigate the effects of HCP on intestinal barrier and microbiota in H1N1 virus infected mice. Mice were infected with H1N1 virus and orally administrated HCP at a dosage of 40 mg(kg−1(d−1. H1N1 infection caused pulmonary and intestinal injury and gut microbiota imbalance. HCP significantly suppressed the expression of hypoxia inducible factor-1α and decreased mucosubstances in goblet cells, but restored the level of zonula occludens-1 in intestine. HCP also reversed the composition change of intestinal microbiota caused by H1N1 infection, with significantly reduced relative abundances of Vibrio and Bacillus, the pathogenic bacterial genera. Furthermore, HCP rebalanced the gut microbiota and restored the intestinal homeostasis to some degree. The inhibition of inflammation was associated with the reduced level of Toll-like receptors and interleukin-1β in intestine, as well as the increased production of interleukin-10. Oral administration of HCP alleviated lung injury and intestinal dysfunction caused by H1N1 infection. HCP may gain systemic treatment by local acting on intestine and microbiota. This study proved the high-value application of HCP.

Non-volatile constituents and pharmacology of Chimonanthus: A review Publication date: March 2019 Source: Chinese Journal of Natural Medicines, Volume 17, Issue 3 Author(s): Ren-Geng SHU, Yi-Li WAN, Xiao-Min WANG Abstract Chimonanthus plants widely distributed in southern area of China, which have a long history of edibles and medicine. Phytochemical investigations have shown that Chimonanthus produced 143 non-volatile constituents, including alkaloids, flavonoids, terpenoids, coumarins and others, which exhibit significant anti-oxidant, anti-bacterial, anti-cancer, anti-inflammatory, antihyperglycemic, antihyperlipidemic and other biological activities. On the basis of systematic reviewing of literatures, this article overviews the non-volatile constituents and pharmacology of Chimonanthus from domestic and foreign over the last 30 years (until June 2018), and may provide a useful reference for the further development of Chimonanthus.

Romipeptides A and B, two new romidepsin derivatives isolated from Chromobacterium violaceum No.968 and their antitumor activities in vitro Publication date: February 2019 Source: Chinese Journal of Natural Medicines, Volume 17, Issue 2 Author(s): Lei XIONG, Chang-Fa CHEN, Tao-Ling MIN, Hai-Feng HU Abstract Romipeptides A and B (1 and 2), two new romidepsin derivatives, and three known compounds, chromopeptide A (3), romidepsin (4) and valine-leucine dipeptide (5) were isolated from the fermentation broth of Chromobacterium violaceum No. 968. Their structures were elucidated by interpretation of their UV, HR-ESI-MS and NMR spectra. The absolute configuration of compound 1 and 2 were established by single crystal X-ray diffraction analysis. Compounds 1–5 were evaluated for their anti-proliferative activities against three human cancer cell lines, SW620, HL60, and A549. The results showed most of these compounds exhibited antitumor activities in vitro, in which compound 2 displayed potent cytotoxicity to SW620, HL60 and A549 cell lines, with IC50 of 12.5, 6.7 and 5.7 nmol·L−1, respectively.

Peptides and polyketides isolated from the marine sponge-derived fungus Aspergillus terreus SCSIO 41008 Publication date: February 2019 Source: Chinese Journal of Natural Medicines, Volume 17, Issue 2 Author(s): Xiao-Wei LUO, Yun LIN, Yong-Jun LU, Xue-Feng ZHOU, Yong-Hong LIU Abstract Two new isomeric modified tripeptides, aspergillamides C and D (compounds 1 and 2), together with fifteen known compounds (compounds 3–17), were obtained from the marine sponge-derived fungus Aspergillus terreusSCSIO 41008. The structures of the new compounds, including absolute configurations, were determined by extensive analyses of spectroscopic data (NMR, MS, UV, and IR) and comparisons between the calculated and experimental electronic circular dichroism (ECD) spectra. Butyrolactone I (compound 11) exhibited strong inhibitory effects against Mycobacterium tuberculosis protein tyrosine phosphatase B (MptpB) with the IC50 being 5.11 ± 0.53 μmol·L−1, and acted as a noncompetitive inhibitor based on kinetic analysis.

Two symmetrical unsaturated acids isolated from Viscum album Publication date: February 2019 Source: Chinese Journal of Natural Medicines, Volume 17, Issue 2 Author(s): Duo CAO, Li-Qing WANG, Xiao-Min HAN, Hui-Rui GUAN, Meng LEI, Ya-Hui WEI, Liang CHENG, Pei-Ming YANG, Zheng-Liang SUN, Wen GAO, Jia-Kun DAI Abstract In the present study, two new acetylene conjugate compounds, dibutyl (2Z, 6Z)-octa-2, 6-dien-4-yne dioate (1), and dibutyl (2E, 6E)- octa-2, 6-dien-4-yne dioate (2), were isolated from the dry stem leaves of Viscum album, along with nine known compounds (3 – 11). Their structures were confirmed on the basis of spectroscopic data. Compounds 1 and 8 showed antioxidant activity against xanthine oxidase (XOD) and 1,1-diphenyl-2-picrylhydrazyl radical 2,2-diphenyl-1-(2,4,6-trinitrophenyl) hydroxyl (DPPH), with the IC50 of 1.22 and 1.33 μmol·L−1, and the SC50 of 4.34 and 8.22 μmol·L−1, respectively.

Vegetation History and Archaeobotany

What was the ecological impact of a Trypillia megasite occupation? Multi-proxy palaeo-environmental investigations at Nebelivka, Ukraine Abstract Fine-resolution sampling of pollen, non-pollen palynomorphs and microcharcoal as well as sedimentological data in a 6-m sediment core were used to reconstruct both natural conditions and human impacts in the late fifth and early fourth millennia cal bc in the environs of the Nebelivka megasite in Kirovograd Oblast, Central Ukraine. This 238-ha site, dating to the Middle (or BII) Phase of the Trypillia culture, represents one of the first low-density urban establishments in Europe. Despite what was believed to be a sizable population, local human impacts reconstructed from the multi-proxy palaeo-ecological record were moderate in character. There was no positive evidence to indicate a depositional hiatus in the P1 core and no sign of a major ecological impact at any stage in the high-resolution record. The palaeo-ecological record indicates modest settlement agglomeration with less permanent populations rather than permanent populations of tens of thousands of people.

Historic landscape and site preservation at Gordion, Turkey: an archaeobotanist's perspective Abstract Archaeobotanical perspectives inform site conservation and presentation at Gordion, Turkey. The historical landscape there includes about 240 royal burial mounds and the archaeological site of Gordion. The tumuli and the historical landscape in which they sit are threatened by agricultural development and suburbanization. The excavated part of the site is exposed to the elements. Protection of the largest tumulus against uncontrolled grazing has reduced erosion and led to biodiversity preservation. Plant management practices coordinated with the architectural conservation team are under development. On stone structures, soft caps are planted with Poa bulbosa and a selective weeding programme aims at keeping deep-rooted plants from destroying the stonework. Education and outreach for local people and tourists include a native plant garden and self-guided walking tours.

Applied archaeobotany of southwest Asia: a tribute to Naomi F. Miller

Ceremonial plant consumption at Middle Bronze Age Büklükale, Kırıkkale Province, central Turkey Abstract A shaft-like room at the Middle Bronze Age site of Büklükale in central Turkey preserved a rich archaeobotanical assemblage of charred and mineralised plant remains, dominated by fruits, spices and nuts mixed with probable bread and wood charcoals. The remains were recovered in association with numerous ceramic vessels, jewellery and exotic artefacts. We combine identification and analysis of the seeds and wood charcoals contained in this deposit with studies of Old Assyrian and Hittite textual records to investigate the circumstances of the assemblage's formation and its significance for further understanding trade and plant consumption in Bronze Age Anatolia. We present the earliest archaeobotanical example in the region of rare and exotic plant species being consumed in the context of one or more social gatherings, including those possibly linked to ceremonial or ritual events. This offers new insights into the role of plants in the economic and social life of the southwest Asian Bronze Age, as well as the role of commensality and feasting in early states.

Cuisine of the Chinese at Market Street Chinatown (San Jose, California): using cookbooks to interpret archaeological plant and animal remains Abstract Archaeobotanical and zooarchaeological remains from Market Street Chinatown, San Jose, California, show that 19th century Chinese migrants ate a varied diet of fruits, vegetables, grains, meat, poultry, and fish. Most of the migrants came from southern China, an area with a well-developed Cantonese cuisine. This article explores how cookbooks can help us interpret the dishes, meals, and activities represented by the remains. 20th-century English-language Chinese cookbooks present guidelines related to meal planning, ingredients, flavours, cooking methods, and dining customs. These culinary principals cannot be applied uncritically to the Market Street Chinatown assemblage. But they help us connect remains from trash pits to food on the table and help us compensate for uneven data stemming from the differential preservation of various plant and animal taxa. Cookbooks indicate that grains are severely underrepresented in the macrofloral record at the site, as are vegetables compared to meat. Recipes show how ingredients could be combined and prepared, and suggest how Euro-American foods were adopted, providing an understanding of daily cooking and dining in 19th century California Chinatowns.

Holocene vegetation cycles, land-use, and human adaptations to desertification in the Gobi Desert of Mongolia Abstract Since the end of the Pleistocene some 11,700 years ago, the landscape and vegetation of the Mongolian Gobi Desert has been profoundly changing, punctuated by the appearance of lakes, wetlands, and finally aridification. Vegetation communities have responded to these changes according to temperature shifts and northward to southward movements of the edges of East Asian monsoonal systems. Human groups have lived, foraged, and traveled through the landscape of the Gobi for millennia, adapting their technologies and systems of plant and animal use with the dramatic changes of flora and fauna, and likely contributed to the character of the vegetation communities in the region today. Pastoral nomads living in semi-arid regions are sometimes implicated as contributors to desertification. However, our research at the Ikh Nart Nature Reserve, Dornogovi Province, Mongolia has yielded geoarchaeological and phytolith data which show the opposite effect. Changing landscape and vegetation patterns from the Middle to Late Holocene suggest that early pastoralists might have contributed to a shift away from halophytic desert vegetation, and an increase in semi-arid desert-steppe grasses. We suggest that the halophytic succulents growing around saline ponds during the Mid-Holocene wet phase, were replaced by Stipa and other steppic grasses after pastoralists entered the region, increasing hillslope erosion which covered the saline sediments of the valley floor, and encouraged the growth of grass seeds carried in the dung of herd animals.

Context and contents: Distinguishing variation in archaeobotanical assemblage formation processes at Early Halaf Fistıklı Höyük, Turkey Abstract Meaningful interpretation of archaeobotanical assemblages in the Near East often includes determination of whether dung fuel is the source of some or all of the recovered plant remains. In the years since Miller (Economy and Environment of Malyan, a Third Millennium B.C. Urban Center in Southern Iran. Ph.D. Dissertation, Department of Anthropology, University of Michigan, Ann Arbor, 1982; Paléorient 10:71–79, 1984) and Miller and Smart (J Ethnobiol 4:15–28, 1984) first identified archaeological plant remains from Malyan (Iran) as those of burned dung, subsequent archaeobotanical, experimental, and ethnographic research has been undertaken to test and expand her criteria for its recognition. A key criterion of Miller's was a high ratio of weed seeds to wood charcoal (or a low ratio of charcoal to weed seeds). When used together with other quantitative measures based on standardizing ratios, this measure can help to illuminate variability in the sources of the recovered carbonized plant remains and some of the taphonomic processes that contributed to the resulting assemblage. Using the Late Early Halaf dataset from Fistıklı Höyük, Turkey, as a case study, non-parametric statistical analysis was applied to eight such measures, including a new Fragmentation Index (FI), density measures (per litre of sediment) for charcoal, cereal grains, weed seeds, chaff, non-wood items, and cereal-type indeterminate non-wood items, and a relative density measure of charcoal to weed seeds. Each measure was calculated on the basis of 35 samples (n = 8,532). The results of this analysis indicate that these measures, when used in combination with Miller's weed seed to charcoal ratio, implemented here as the relative density of charcoal to weed seeds, can reveal recovery context-related variations in formation processes that help to clarify both the role of dung fuel in assemblage formation and to differentiate the remains of cereal processing from those of burned fuel.

The burning issue of dung in archaeobotanical samples: a case-study integrating macro-botanical remains, dung spherulites, and phytoliths to assess sample origin and fuel use at Tell Zeidan, Syria Abstract Since Naomi Miller's first discussion of dung fuel within macro-botanical samples from Malyan, Iran, considerations of dung fuel across Southwest Asia have become commonplace, yet archaeobotanists remain divided on: (1) the extent to which dung fuel contributed to archaeobotanical assemblages relative to remnants of repeated crop processing and household activities; and (2) the plant-based, middle-range theories that should be used to infer the presence of dung within macro-botanical assemblages. Here we present a case-study integrating a simple, well-established geo-archaeological approach to assess the presence and relative abundance of dung spherulites within paired sediment and flotation samples from Ubaid period Tell Zeidan, Syria (5300–5100 bc). Spherulite data generated from "sediment smears" are integrated with macro-botanical and phytolith data to assess elevated concentrations of dung within samples. Our analyses demonstrate that plant-based depositional processes across a site are complex, reflecting the rich nature of plant use in antiquity. By using a multi-proxy approach, it is possible to differentiate between predominantly fuel-based deposits and those resulting from predominantly crop-processing processes with greater resolution. This study documents the use of wood fuels in hearths and dung fuel within pyrotechnic features and an oven during the Ubaid period, thereby contributing to discussions of fuel selection and the Secondary Products Revolution. When spherulites are preserved within sediment in abundance, they are also present in floated material, so it is possible to use this approach to consider the presence of dung within archived macro-botanical samples and resolve decade-old debates.

The lost dimension: pruned plants in Roman gardens Abstract This paper focuses on evidence for the pruning and dwarfing of plants represented in Roman garden paintings. In two particularly fine examples of this type, from the Villa of Livia at Prima Porta near Rome, and the House of the Golden Bracelet at Pompeii, the artists have carefully portrayed pruning marks and other horticultural practices that alter the size and natural habit of plants. This evidence complements archaeobotanical findings by showing the above-ground appearance of garden plants attested in the archaeological record. The remains of a garden that may be linked to garden paintings were found in 2007 in the Great Peristyle at the Villa Arianna at Stabiae, near Pompeii. Seeking evidence for the interpretation of this garden, paintings and texts have been critically examined. The results reveal a wealth of evidence for plant pruning management in the paintings linked to nemora tonsilia or silva tonsilia—the art of pruning groups of trees and shrubs for ornamental presentation, initiated by C. Matius during the reign of Augustus in the 1st century bc. This art of pruning woody plants may be a virtuoso display of the horticultural skills involved in the management of the broader cultivated landscape of Rome and Pompeii.

Dung burning in the archaeobotanical record of West Asia: where are we now? Abstract In the early 1980s Naomi Miller changed the field of palaeoethnobotany; her research into whether the ancient seed eaters of southwest Asia were human or herbivore opened an ongoing debate over the impact that burning of animal dung had on the formation of archaeobotanical assemblages, and how researchers can differentiate between human and animal food remains. As the number of systematic archaeobotanical studies across West Asia and many other parts of the world increase, we are continually confronted with the question of the significance of dung burning. Herd animal dung is the dominant fuel source in many parts of West Asia today and the high densities of seeds of wild plants in archaeobotanical assemblages suggest that people were using dung as fuel across Inner Asia for millennia. Seed assemblages that represent herd animal dung are assisting scholars in understanding palaeoecology and herd animal diet in the past as well as human economy and pasturing practices. However, interpreting these assemblages is not always simple and there are predictable biases that need to be taken into account, notably an overrepresentation of endozoochoric seeds (seeds dispersed through animal ingestion). In West Asia, the most prominent of such seeds in dung assemblages are from the Amaranthaceae family, notably Chenopodium.

CardioVascular and Interventional Radiology

Intratumoral Injection of Hypertonic Glucose in Treating Refractory Pneumothorax Caused by Microwave Ablation: a Preliminary Study Abstract Purpose The purpose of this technical report is to describe the technique of intratumoral injection of hypertonic glucose combined with low-negative pressure drainage to treat refractory pneumothorax (RP) after microwave ablation (MWA) of lung tumors. Materials and Methods Between September 2016 and May 2018, four patients who developed RP after MWA of peripheral lung cancer were managed by a combined method, including intratumoral injection of hypertonic glucose and catheter drainage under low-negative pressure. Blood gas values were recorded and compared before the treatment and one-week posttreatment. All patients were followed up for at least one month to monitor the possible recurrence of pneumothorax by chest CT. Results All patients were successfully treated. One patient received the intratumoral injection of hypertonic glucose twice, while the remaining three patients received a single injection. The technical success rate was 100%. Dyspnea related to RP was significantly relieved in all patients, and PaO2 and SaO2 values were higher than those measured before treatment. No patient suffered a recurrence of pneumothorax during the follow-up. Conclusion The combined method of intratumoral injection of hypertonic glucose and continuous catheter drainage under low-negative pressure might be an effective method to manage RP caused by MWA.

Imaging Neuroendocrine Hepatic Metastases Following 90 Y-Radioembolization: Is It Time to Implement Routine Use of PET Molecular/Metabolic Probes?

Patient Reported Outcomes in Interventional Radiology: Time to Measure What We Do

Combined Y-Shaped Covered Metallic Stents for Gastrobronchial Fistulas Involving the Right Intermediate Bronchus Abstract Gastrobronchial fistula that involves the right intermediate bronchus is an extremely rare complication of esophagectomy. In this report, two patients with gastrobronchial fistulas around the secondary right carina were treated by combined Y-shaped covered metallic stents. Four covered stents were inserted successfully at the first attempt with no complications. The gastrobronchial fistula was fully sealed in each patient, and they were able to eat without coughing.

Recycling in IR, What IR Specialists Can Do to Help

Balloon-Occluded Transcatheter Arterial Chemoembolization (b-TACE) for Hepatocellular Carcinoma Performed with Polyethylene-Glycol Epirubicin-Loaded Drug-Eluting Embolics: Safety and Preliminary Results Abstract Purpose To report technical success, safety profile and oncological results of balloon-occluded transcatheter arterial chemoembolization using a balloon micro-catheter and epirubicin-loaded polyethylene-glycol (PEG) microsphere (100 ± 25 µm and 200 ± 50 µm) in patients with hepatocellular carcinoma (HCC). Materials and Methods This is a single-centre, single-arm, retrospective study with 6-month follow-up. Twenty-two patients (Child–Pugh A 68% [15/22], B in 32% [7/22]; age 67.05 ± 14 years) with 29 HCC were treated in 24 procedures. Technical success is defined: ability to place the balloon micro-catheter within the required vascular segment, balloon-occluded arterial stump pressure drops and assessment of microsphere deposition. Laboratory assessment pre/post-procedural and complications were analysed, respectively, according to Common Terminology Criteria for Adverse Events (CTCAEv5) and CIRSE system. Postembolization syndrome (PES) was defined as fever and/or nausea and/or pain onset. Oncological results were evaluated using m-RECIST criteria with CT/MRI imaging at 1 and 3–6 months. In partial responder patients, pre/post-procedural tumour volume was compared. Results Pre-planned feeder was reached in all cases. Pressure drop average was 51.1 ± 21.6 mmHg. Exclusive target embolization was achieved in 14/24 procedures (58.3%). Laboratory test modifications were all grade 1. 4/24 adverse events occurred (17%): pseudo-aneurysm of the feeder (grade 3), liver abscess (grade 2) and 2 asymptomatic segmentary biliary tree dilatations (grade 2). PES occurred in 8/24 (33%). The complete response at 1 and 3–6 months was 44.8% (13/29) and 52.9% (9/17), respectively. The partial response at 1 and 3–6 months was 55% (16/29) and 4/17 (23.5%), respectively. Among partial responder patients, the average percentage of tumour volume reduction was 64.9 ± 27.3%. Conclusion Epirubicin-loaded PEG microsphere b-TACE is technically feasible, safe and effective procedure for HCC treatment.

Transarterial (Chemo-)Embolization and Lipiodolization for Hepatic Haemangioma Abstract Background Transarterial (chemo-)embolization/lipiodolization (TAE/TAL) might be an attractive minimally invasive alternative to surgery in the treatment of symptomatic hepatic haemangioma. This review assesses the efficacy and safety of TAE/TAL as primary treatment for symptomatic hepatic haemangioma. Methods A systematic search of the literature was performed by two reviewers following the PRISMA guidelines. Cohort studies and case reports were identified; outcomes of cohort studies were reported. The primary efficacy outcome was tumour size before and after TAE/TAL. Improvement of symptoms and quality of life (QoL) were secondary outcomes; the primary safety outcome was complications. The Downs and Black statement was used for quality assessment. Results Eighteen cohort studies were identified, including 1284 patients. TAE/TAL led to a decrease in tumour size in 1100/1223 (89.9%) patients and to improvement or disappearance of symptoms in 1080/1096 (98.5%) patients. A significant decrease in tumour size from 9.79 ± 0.79 cm to 4.00 ± 1.36 cm (p < 0.001) was shown. Grade 3 complications occurred in 37/1284 (2.9%) patients. Surgical treatment was necessary in 35/1284 (2.7%) of patients. Conclusion TAE/TAL appears to be a promising and safe treatment to decrease tumour size of hepatic haemangioma. The technique might also provide partial relief of symptoms, although no randomized clinical trials or prospective studies using validated QoL questionnaires are available. TAE/TAL may be considered as a viable alternative to resection.

Lymphangiography and Lymphatic Embolization for the Management of Pelvic Lymphocele After Radical Prostatectomy in Prostatic Cancer Abstract Purpose To retrospectively evaluate the short-term outcomes of lymphangiography and lymphatic embolization in the treatment of pelvic lymphocele after radical prostatectomy in patients with prostate cancer. Materials and Methods The data of nine, consecutive patients who underwent lymphangiography and lymphatic embolization for pelvic lymphocele after radical prostatectomy with pelvic lymph node dissection (PLND) between January 2016 and May 2018, were retrospectively reviewed. Lymphangiography was performed through inguinal lymph nodes in order to identify the lymphatic leakage. When a leakage was found, lymphatic embolization was performed using a directly punctured fine needle at the closest upstream lymph node or lymphopseudoaneurysm and with N-butyl cyanoacrylate glue. Results Lymphangiography demonstrated extravasation and/or lymphopseudoaneurysm in all of these patients. A total of 13 sessions of lymphangiography and lymphatic embolization were performed. The median number of lymphangiography and lymphatic embolizations required to achieve clinical success was one (range, 1–3). Three patients underwent repeated embolization with successful results. The technical and clinical success rates were 100%, respectively. The median time to resolution was 7 days (range, 2–19 days). There was no recurrence and no procedure-related complications during the follow-up period (mean, 26 weeks; range, 8–77 weeks) in all patients. Conclusions Lymphangiography and lymphatic embolization are safe and effective for the management of pelvic lymphoceles after radical prostatectomy with PLND.

Does Drug-Eluting Bead TACE Enhance the Local Effect of IRE? Imaging and Histopathological Evaluation in a Porcine Model Abstract Objectives We conducted an in vivo trial on swine to compare the ablation volumes of irreversible electroporation (IRE) followed by drug-eluting beads transarterial chemoembolization (DEB-TACE) versus IRE only. Materials and Methods Nine swine underwent CT-guided IRE in one liver lobe and IRE immediately followed by DEB-TACE in a different liver lobe. For DEB-TACE, 100–300 µm beads (DC-Beads®) were loaded with 50 mg doxorubicin. For IRE, the NanoKnife® was used employing two electrodes according to the vendor's protocol. Imaging follow-up was performed including CT-based lesion volume assessment using contrast-enhanced CT (venous phase) on days 1, 3, and 7 after the procedure. Three animals were killed for histopathological analysis after each follow-up. Results Ablation volumes in CT in the IRE + DEB-TACE group were 15.4 ± 10.5 ml on day 1, 8.7 ± 5.6 ml on day 3, and 1.6 ± 0.7 ml on day 7. In the IRE group, the corresponding values were 5.2 ± 5.2 ml on day 1, 1.0 ± 1.2 ml on day 3, and 0.1 ± 0.1 ml on day 7. On day 1 and day 3, ablation volumes of IRE + TACE group were significantly larger than in the IRE group (p < 0.05). 96% of beads were depicted in or around ablative lesions. 69% of these beads were found in the surrounding hemorrhagic infiltration and 31% within the ablative lesion itself. Conclusions Combination of IRE immediately followed by DEB-TACE resulted in larger ablation volumes compared to IRE alone, suggesting that local efficacy of IRE can be enhanced by post-IRE DEB-TACE.

Endovascular Recanalization of Thromboangiitis Obliterans (Buerger's Disease) in Twenty-Eight Consecutive Patients and Combined Antegrade–Retrograde Intervention in Eight Patients Abstract Purpose The aim of the study was to evaluate the technical success of the procedure and the clinical efficacy of treatment in patients with thromboangiitis obliterans (TAO) (Buerger's disease) based on a change in the Rutherford classification. Materials and Methods A total of 28 consecutive patients (26 males, 2 females, mean age 43.3 ± 5.32 years) underwent endovascular recanalization with a diagnosis of TAO, between April 2015 and July 2018. After unsuccessful attempts using the antegrade approach, retrograde approaches were used in 8 patients under ultrasound guidance. Clinical follow-up was routinely performed at 1-month, 3-month, 6-month, and 1-year intervals. Results A total of 28 TAO patients underwent 40 procedures in 32 limbs. Technical success was achieved in 28 of the 32 limbs (87.5%). In total, 45 of 59 (76.2%) below the knee arteries were treated successfully. One major amputation was performed, providing a 96.8% rate for limb salvage both at 12 and 24 months. Amputation-free survival estimated by Kaplan–Meier analysis was 84% at 12 and 24 months. Primary patency rates at 12, 24, and 36 months were 84%, 78%, and 75%, respectively. Secondary patency rates were 87.5% both at 12 and 24 months. Conclusion Endovascular treatment is a technically feasible and potentially effective treatment modality for Buerger's disease. Combined antegrade and retrograde interventions in TAO patients may improve technical success and clinical recovery, especially in cases where the antegrade approach has failed.

Cancer Chemotherapy and Pharmacology

FLAG vs FLAG-IDA: outcomes in relapsed/refractory acute leukemias Abstract Background FLAG (fludarabine, cytarabine, granulocyte colony—stimulating factor) and FLAG-IDA (idarubicin added to standard FLAG) are salvage chemotherapy regimens used for relapsed and refractory acute leukemias. The toxicity of the FLAG-IDA courses is generally more severe than for the FLAG courses, with marked neutropenia and thrombocytopenia. This study aims to compare the outcomes of both regimens in terms of morbidity, mortality and remission/transplant. No comparison has been reported so far in Pakistan or the rest of third world countries. Methodology This retrospective study was conducted in Hematology and Bone Marrow Transplant unit after approval from Institutional Review Board and Ethics Committee. 76 leukemic patients treated with salvage chemotherapy were included. Our endpoints for patient outcome analysis included disease remission/relapse, HSCT following remission, morbidity, mortality, progression free survival and overall survival. Kaplan Meier curves were made in SPSS for survival analysis. Results A total of 76 patients were included from 2015 to July 2018. 49 patients were given FLAG, and 27 were given FLAG-IDA. 31.6% in FLAG-IDA achieved complete remission (CR)/complete remission with incomplete counts (CRi). 21% in FLAG-IDA made it to Bone marrow transplant (BMT) (67% of those in CR/CRi). 41.7% in FLAG achieved CR/CRi, and 27.8% in FLAG made it to BMT (67% of those in CR/CRi). Common complications in both regimens were infection, bleeding and other complications e.g., rash, diarrhea, mucositis, etc. A statistically significant difference was found between overall survival of the two regimens, p value 0.033. Conclusions FLAG regimen was found superior to FLAG-IDA with better survival and subsequent transplant rate.

Short-time use of crizotinib as neoadjuvant in ALK-positive non-small cell lung carcinoma can be a chance for resectability Abstract Because of the rapid response to crizotinib, patients with ALK-positive locally advanced disease may become resectable with the use of neoadjuvant crizotinib. A 41-year-old never-smoking man who presented with asthma attack was found to have a suspicious lesion on chest X-ray after. Pathological examination was consistent with ALK(+), the signet-ring cell adenocarcinoma. Surgery was not performed because of mediastinal invasion of the mass. After 4 weeks of crizotinib treatment, a major response was achieved and the tumor became completely cavitary. Short-term neoadjuvant therapy with crizotinib for 4 weeks might be a promising therapy in locally advanced ALK-positive NSCLC and might provide a chance for resectability.

Rabeprazole intake does not affect systemic exposure to capecitabine and its metabolites, 5′-deoxy-5-fluorocytidine, 5′-deoxy-5-fluorouridine, and 5-fluorouracil Abstract Purpose Several retrospective studies have shown that the antitumor efficacy of capecitabine-containing chemotherapy decreases when co-administered with a proton pump inhibitor (PPI). Although a reduction in capecitabine absorption by PPIs was proposed as the underlying mechanism, the effects of PPIs on capecitabine pharmacokinetics remain unclear. We prospectively examined the effects of rabeprazole on the pharmacokinetics of capecitabine and its metabolites. Methods We enrolled patients administered adjuvant capecitabine plus oxaliplatin (CapeOX) for postoperative colorectal cancer (CRC) patients and metastatic CRC patients receiving CapeOX with/without bevacizumab. Patients receiving a PPI before registration were allocated to the rabeprazole group, and the PPI was changed to rabeprazole (20 mg/day) at least 1 week before the initiation of capecitabine treatment. On day 1, oral capecitabine (1000 mg/m2) was administered 1 h after rabeprazole intake. Oxaliplatin (and bevacizumab) administration on day 1 was shifted to day 2 for pharmacokinetic analysis of the first capecitabine dose. Plasma concentrations of capecitabine, 5′-deoxy-5-fluorocytidine, 5′-deoxy-5-fluorouridine, and 5-fluorouracil were analyzed by high-performance liquid chromatography. Effects of rabeprazole on inhibition of cell proliferation by each capecitabine metabolite were examined with colon cancer cells (COLO205 and HCT116). Results Five and 9 patients enrolled between September 2017 and July 2018 were allocated to rabeprazole and control groups, respectively. No significant effects of rabeprazole on area under the plasma concentration–time curve divided by capecitabine dose for capecitabine and its three metabolites were observed. Rabeprazole did not affect the proliferation inhibition of colon cancer cells by the respective capecitabine metabolites. Conclusion Rabeprazole does not affect capecitabine pharmacokinetics.

Phase II study to evaluate the efficacy of Trastuzumab in combination with Capecitabine and Oxaliplatin in first-line treatment of HER2-positive advanced gastric cancer: HERXO trial Abstract Purpose The phase III ToGA trial established cisplatin, fluoropyrimidine and trastuzumab as the standard treatment in HER2-positive advanced gastric cancer (AGC). However, as demonstrated in HER2-negative AGC, oxaliplatin-based regimens could improve tolerance remaining effective. The aim of this trial was to explore the potential activity and safety of capecitabine, oxaliplatin (XELOX) and trastuzumab in patients with HER-2 positive advanced gastric cancer. Methods We conducted a multicentre, prospective, non-randomised, non-controlled, open-label and national (Spanish) phase II study. Patients with HER2-positive advanced gastric or gastro-oesophageal junction (EGJ) cancer received XELOX and trastuzumab as first-line treatment. Primary endpoint was objective tumour response rate (ORR). Results 45 patients from ten hospitals in Spain were included from September 2011 to December 2013. Median age was 65 years, 82.2% were male, 69% had gastric cancer and 31% had EGJ tumours. At a median follow-up of 13.7 months (7.1–20.9), the estimated median progression-free survival and overall survival were 7.1 (95% CI 5.5–8.7) and 13.8 months (95% CI 10.1–17.4), respectively, with 8.9%, 37.8% and 31.1% of patients achieving complete response, partial response and stable disease. Regarding safety, 44.4% of the patients had grade 3 or greater adverse events, being the most frequent diarrhoea (26.6%), fatigue (15.5%), nausea (20%) and vomiting (13.3%). Only two patients (4.4%) developed asymptomatic grade 2 left ventricle ejection fraction reduction. Conclusions XELOX-trastuzumab is a promising and effective therapy as first-line treatment for patients with HER2-positive AGC, with comparable results to the ones obtained with other "platinum-based" regimens. This scheme is feasible and tolerable with a low incidence of cardiac toxicity.

d,l -Methadone does not improve radio- and chemotherapy in glioblastoma in vitro Abstract Purpose Glioblastoma (GBM) is the most common malignant tumor of the central nervous system. Median survival of glioblastoma patients under standard therapy including radiotherapy and chemotherapy using temozolomide (TMZ) is 14.6 months. As cell culture experiments combining d,l-methadone with doxorubicin demonstrated an increased reduction of cell viability of glioblastoma cells, the opioid has been discussed as a drug for the treatment of GBM. Despite lack of clinical and experimental evidence that d,l-methadone in combination with standard therapy will be beneficial, an increasing number of tumor patients medicating themselves with d,l-methadone present to the hospitals in Germany. Methods As a first step towards understanding whether d,l-methadone may increase the efficacy of standard therapy, we used a cell culture model of primary GBM and fibroblast cell cultures derived from GBM patients. The cultures were treated with different concentrations of d,l-methadone in combination with X-irradiation, TMZ or both. Cell viability was determined by measuring ATP in cell lysates and dehydrogenase activity in living cells. Results When only treated with d,l-methadone, 1 µM of the opioid was sufficient to reduce viability of fibroblasts, whereas 10 µM was needed to significantly reduce glioblastoma cell viability. In addition, d,l-methadone did not improve the anti-neoplastic effects of X-irradiation, temozolomide or both. Conclusions As d,l-methadone reduces glioblastoma cell viability only when concentrations are used that had been reported to be toxic to patients and as there were no interactions observable combining it with standard therapy, a recommendation for the use of d,l-methadone in glioblastoma therapy cannot be given.

Docetaxel, cisplatin, and 5-fluorouracil combination chemoradiotherapy for patients with cervical esophageal cancer: a single-center retrospective study Abstract Background To evaluate the efficacy of docetaxel, cisplatin, and 5-fluorouracil as combination chemoradiotherapy (DCF-RT) for cervical esophageal cancer (CEC), we performed a retrospective analysis of CEC patients treated by DCF-RT at a single institution. Methods We conducted a single-center retrospective study. Twenty-one patients with CEC who underwent DCF-RT between 1999 and 2017 at our institute were included in this study. Chemotherapy consisted of intravenous docetaxel at 50 mg/m2 on day 1, intravenous CDDP at 60 mg/m2 on day 1, and intravenous 5-FU at 600 mg/m2 on days 1–4, repeated every 4 weeks for two cycles. Among the 21 patients, six were irradiated using three-dimensional conformal RT (3D- conformal RT) and 15 were treated using intensity-modulated RT (IMRT) consisting of 60 Gy in 30 fractions. Results The median follow-up period was 49.6 months (range 4.6–97.6). The overall complete response (CR) and local CR rates were 61.9% and 81.0% for all patients, and 76.9% and 84.6% for patients without hypopharyngeal and/or thoracic esophageal invasion, respectively. The 3-year overall survival (OS), progression-free survival (PFS), and local failure-free survival (LFFS) rates were 79.6, 52.4, and 74.7%, respectively. Grade 3–4 leucopenia developed in 12 patients (70.6%), neutropenia developed in 13 patients (81.2%), and mucositis developed in 2 patients (9.5%). There were no treatment-related deaths. Conclusions The 3-year OS and LFFS of patients who underwent DCF-RT were higher than those in the previous studies. Although the high rate of myelosuppression requires careful management, DCF-RT is a safe and effective modality for CEC.

Apatinib for chemotherapy-refractory extensive-stage SCLC: a retrospective study Abstract Purpose There is no standard treatment strategy for patients with extensive-stage small cell lung cancer (SCLC) who have failed two or more prior chemotherapeutic regimens. In this study, we retrospectively evaluated the efficacy and safety of apatinib in patients with extensive-stage SCLC after failure of more than second-line chemotherapy. Methods A study group comprised of 22 patients with extensive-stage SCLC after failure of more than two prior chemotherapeutic regimens was given apatinib orally at an initial dose of 500 mg daily until disease progression or unacceptable toxicity. This study was analyzed according to the National Cancer Institute Common Toxicity Criteria for adverse events (AEs) and Response Evaluation Criteria in Solid Tumors (RECIST) for response assessment. Results Between August 30, 2015, and May 26, 2017, 22 patients were enrolled for evaluating the efficacy and safety of apatinib. Among them, 12/22 (54.5%) underwent dose reduction during treatment. Up to July 31, 2018, the median progression-free survival rate was 135.0 days [95% confidence interval (CI) 63.8–206.2]. According to the RECIST criteria, the disease control rate (DCR) was 86.4%, 19/22 [comprised of partial response (PR) 18.2%, 4/22; and stable disease (SD) 68.2%, 15/22 patients]. The most frequent AEs were hand–foot syndrome (45.5%, 10/22), secondary hypertension (45.5%, 10/22) and fatigue (40.9%, 9/22). The primary grade 3 or 4 toxicities were hypertension (22.7%, 5/22), hand–foot syndrome (13.6%, 3/22), and proteinuria (9.1%, 2/22). Conclusions Apatinib exhibits modest activity and acceptable toxicity for patients with heavily pretreated extensive-stage SCLC.

Pharmacokinetic and exploratory exposure–response analysis of pertuzumab in patients with operable HER2-positive early breast cancer in the APHINITY study Abstract Purpose To characterize the pharmacokinetics (PK) of, and perform an exploratory exposure–response (E–R) analysis for, pertuzumab in patients with HER2-positive early breast cancer (EBC) within the APHINITY study (NCT01358877, BIG 4–11/BO25126/TOC4939G). Methods A previously developed pertuzumab two-compartment linear population pharmacokinetic (popPK) model was subjected to external validation to examine appropriateness for describing pertuzumab concentrations from the APHINITY study. Pharmacokinetic drug–drug interactions (DDIs) between pertuzumab, trastuzumab, and chemotherapy were assessed by comparing observed serum or plasma Cmax, Cmin, and AUClast geometric mean ratios with 90% CIs. Predictions of pertuzumab Cmax,ss, Cmin,ss, and AUCss were derived from individual parameter estimates and used in an exploratory E–R analysis. Results Using data from 72 patients, based on goodness-of-fit, the popPK model was deemed appropriate for predictions of individual exposures for subsequent comparisons to historical data, assessment of DDIs, and E–R analyses. No evidence of DDIs for pertuzumab on trastuzumab, trastuzumab on pertuzumab, or pertuzumab on chemotherapy PK was observed. Analyses of differences in exposure between patients with and without invasive disease-free survival events did not indicate improved efficacy with increased exposure. Overall Grade ≥ 3 diarrhea prevalence was higher with pertuzumab versus placebo, but was not greater with increasing pertuzumab exposure. No apparent E–R relationship was suggested with respect to other grade ≥ 3 AEs. Conclusion Overall, the limited available data from this exploratory study suggest that no dose adjustments are needed for pertuzumab when administered in combination with trastuzumab and an EBC chemotherapy regimen.

Placental growth factor is a predictive biomarker for ramucirumab treatment in advanced gastric cancer Abstract Purpose Ramucirumab (RAM) has been used as the second-line standard chemotherapy for advanced gastric cancer (AGC) either alone or combination with paclitaxel (PTX). However, no predictive biomarkers have been identified for RAM treatment in AGC. Methods We retrospectively identified 26 patients who received either RAM monotherapy or RAM + PTX therapy for AGC refractory to fluoropyrimidine and platinum agents from 2015 to 2018 at Nagoya City University Hospital. First, we extracted RNA using gastric cancer (GC) tissues from two responders and two non-responders, and then analyzed 24 VEGFR-related angiogenic genes. Subsequently, we examined the relationship between the expression of each angiogenic gene and RAM clinical activity in the entire cohort. Finally, we validated using in vitro angiogenesis assays using GC cells and microvascular endothelial cells. Results We identified five angiogenic genes with aberrant expression between RAM responders and non-responders and placental growth factor (PlGF) was the most significant gene among them. Overall survival (P = 0.046) and progression-free survival (P = 0.016) were significantly shorter in the PlGF-high group than in the PlGF-low group. Overall response rates were 50% in the PlGF-low group and 0% in the PlGF-high group. In GC cells co-cultured with endothelial cells, PlGF gene silencing from GC cells significantly reinforced the inhibitory effect of RAM in the in vitro angiogenesis assay (tube formation assay and endothelial migration) through the inactivation of ERK, in comparison to the control GC cells. Conclusions PlGF gene expression in gastric cancer tissues could be a predictive indicator of AGC treatment by RAM.

A phase I study of gemcitabine + dasatinib (gd) or gemcitabine + dasatinib + cetuximab (GDC) in refractory solid tumors Abstract Purpose This study was conducted to define the maximum tolerated dose (MTD), recommended phase two dose (RPTD), and toxicities of gemcitabine + dasatinib (GD) and gemcitabine + dasatinib + cetuximab (GDC) in advanced solid tumor patients. Methods This study was a standard phase I 3 + 3 dose escalation study evaluating two combination regimens, GD and GDC. Patients with advanced solid tumors were enrolled in cohorts of 3–6 to either GD or GDC. Gemcitabine was dosed at 1000 mg/m2 weekly for 3 of 4 weeks, dasatinib was dosed in mg PO BID, and cetuximab was dosed at 250 mg/m2 weekly after a loading dose of cetuximab of 400 mg/m2. There were two dose levels for dasatinib: (1) gemcitabine + dasatinib 50 mg ± cetuximab, and (2) gemcitabine + dasatinib 70 mg ± cetuximab. Cycle length was 28 days. Standard cycle 1 dose-limiting toxicity (DLT) definitions were used. Eligible patients had advanced solid tumors, adequate organ and marrow function, and no co-morbidities that would increase the risk of toxicity. Serum, plasma, and skin biopsy biomarkers were obtained pre- and on-treatment. Results Twenty-five patients were enrolled, including 21 with pancreatic adenocarcinoma. Three patients received prior gemcitabine. Twenty-one patients were evaluable for toxicity and 16 for response. Four DLTs were observed: Grade (Gr) 3 neutropenia (GDC1, n = 1), Gr 3 ALT (GD2, n = 2), and Gr 5 pneumonitis (GDC2, n = 1). Possible treatment-emergent adverse events (TEAEs) in later cycles included: Gr 3–4 neutropenia (n = 7), Gr 4 colitis (n = 1), Gr 3 bilirubin (n = 2), Gr 3 anemia (n = 2), Gr 3 thrombocytopenia (n = 2), Gr 3 edema/fluid retention (n = 1), and Gr 3 vomiting (n = 3). Six of 16 patients (3 of whom were gemcitabine-refractory) had stable disease (SD) as best response, median duration = 5 months (range 1–7). One gemcitabine-refractory patient had a partial response (PR). Median PFS was 2.9 months (95% CI 2.1, 5.8). Median OS was 5.8 months (95% CI 4.1, 11.8). Dermal wound biopsies demonstrated that dasatinib resulted in a decrease of total and phospho-Src levels, and cetuximab resulted in a decrease of EGFR and ERBB2 levels. Conclusions The MTD/RPTD of GD is gemcitabine 1000 mg/m2 weekly for 3 of 4 weeks and dasatinib 50 mg PO BID. The clinical activity of GD seen in this study was modest, and does not support its further investigation in pancreatic cancer.