National Academy Science

An Improved Server Validation Scheme for Multi-server Infrastructure Abstract An improved server validation scheme for a multi-server infrastructure has been introduced. In this scheme, each member involved in communication has to prove its validation before any exchange of information bits. This introduced scheme also secures the server against phishing and other similar attacks. Dynamic properties of the group are handled with ease, making the scheme suitable for real-life applications. Major achieved highlights of the method are that user privacy is respected without requiring any serious time synchronization.

Passenger Car Active Suspension System Model for Better Dynamic Characteristics Abstract The technological investigations to a light passenger car have been carried out in order to improve the comfort and safety features by the implementation of an active suspension system. A fuzzy logic control-based active suspension system is proposed for the fuel-efficient small passenger cars to fulfil the design upgradation requirements. The proposed design comprised of hydraulically powered actuators is installed at each of the car wheels between sprung and unsprung mass to compensate the ground forces in order to resolve the instability and comfort issues. The dynamic analysis figures out the significant improvement of 12% in comfort and 11.53% in the car stability.

Power Consumption-Based Dynamic Network Selection in Heterogeneous Networks Abstract Network selection is a critical task for mobile terminals moving in heterogeneous environment of next-generation wireless networks. Power consumption of mobile terminal is a matter of great concern in the present scenario for efficient network selection in integrated network of various wireless technologies. In this paper, multiple attributes decision-making-based dynamic network selection method PV–VPP is proposed by considering power consumption of mobile terminal at instantaneous battery level in heterogeneous networks.

Reducing Reconfiguration Overheads Using Configuration Prefetch, Optimal Reuse, and Optimal Memory Mapping Abstract Modern embedded systems are packed with dedicated field-programmable gate arrays (FPGAs) to accelerate the overall system performance. But the main drawback in using FPGA as a reconfigurable system is that a lot of reconfiguration overheads are generated in the reconfiguration process. The reconfiguration overheads are mainly because of the configuration data being fetched from the off-chip memory and also due to the improper management of tasks during execution. This work focusses mainly on the prefetch heuristics, reuse technique, and the available memory hierarchy to provide an efficient management of tasks over the available resources. This short communication proposes a new optimal replacement policy which reduces the overall time and energy reconfiguration overheads for static systems in their subsequent iterations. It is evident from the results that most of the time and energy reconfiguration overheads are eliminated.

q -Double Cesaro Matrices and q -Statistical Convergence of Double Sequences Abstract In this study, we introduce and examine the concepts of q-double Cesaro matrices and q-statistical convergence and q-statistical limit point of double sequences. Also, we give some relations connected to these concepts.

A Note on the Rainbow Neighbourhood Number of Certain Graph Classes Abstract A rainbow neighbourhood of a graph G is the closed neighbourhood N[v] of a vertex \(v \in V(G)\) which contains at least one colored vertex of each color in the chromatic coloring \({\mathscr {C}}\) of G. Let G be a graph with a chromatic coloring \({\mathscr {C}}\) defined on it. The number of vertices in G yielding rainbow neighbourhoods is called the rainbow neighbourhood number of the graph G, denoted by \(r_\chi (G)\) . In this paper, rainbow neighbourhood number of certain graph classes are discussed.

Report on Wild Eri Silkworm Samia canningii Hutton (Lepidoptera: Saturniidae) from Arunachal Pradesh, India Abstract This study was conducted to study morphology of the life stages of wild eri silkworm Samia canningii Hutton from Arunachal Pradesh, India, which is the easternmost part of Himalaya biodiversity hotspot. Fifth instar larvae are of three forms: (1) bluish white, (2) yellow and (3) bluish green. Colour of tubercle like projections in bluish white and bluish green larvae is blue in 5th instar. In yellow form, projections are yellow. Legs are orange in colour in all colour morphs. White powdery substance appears from 3rd instar larvae. Colour of newly spinned cocoon of S. canningii is bright yellow. Later, it turns to brown. Cocoons are open ended like Samia cynthia ricini. Matured larvae—median length of abdomen 62–65 mm, median body width 9–10 mm. Cocoon—median length 27–33 mm, Median breadth 12–14 mm.

New report of Trachyphyllum borgenii (Renauld & Cardot) Broth. (Bryophyta) from India with a Note on Its Disjunct Distribution in Madagascar Abstract The present study highlights the disjunct distribution of the moss Trachyphyllum borgenii (Renauld & Cardot) Broth. Trachyphyllum borgenii, was earlier known as an endemic to Madagascar, has recently been identified at Pachmarhi Biosphere Reserve (PBR), central India. The discovery of T. borgenii is a new record for Indian subcontinent with extended range of distribution from Madagascar and now it can be designated as a species with disjunct distribution instead of an endemic species.

Omnidirectional Radio Propagation Antenna Using Organized Grouping of Monopole Antennas Abstract An omnidirectional radio propagation antenna is designed in the present study by grouping three microstrip monopole antennas of MRF24J40MA transceiver on a transmitter device. MRF24J40MA transceiver is operating at 2.4 GHz of frequency with maximum transmission power of 0 dBm and receiving sensitivity of − 91 dBm. The proposed antenna radiating characteristic is tested by measuring the maximum received signal strength indicator along the angular direction from 0 to 360 degree. The main objective of this letter is to authenticate the work of various localization algorithms based on oversimplification of radio propagation model.

An Efficient Hybrid User Profile Based Web Search Personalization Through Semantic Crawler Abstract The World Wide Web has a collection of trillions of web pages and these web pages are increasing day by day. Web pages available on the Web change frequently and these changes are sometimes unnoticeable by the end user. The exponential growth of web documents on the Internet makes it difficult to find out which are the most relevant web documents for a particular end user on a given search query and user spends a lot of time to get relevant information. The proposed web search personalization system successfully identifies preferences of the end user and constructs an efficient user profile for every end user. It utilizes the built web page repository by retrieving web search results and personalizes them according to user preferences. It is also capable to handle ambiguous queries. The proposed system increases the search accuracy by 37.6% over existing agent based personalization system.

East European Thought

Lenin without dogmatism Abstract A longstanding criticism of Lenin is that his epistemological contributions to the theory of scientific socialism prompted the decline of Marxism in dogmatism and despotism in the twentieth century. According to this narrative, Lenin claimed to possess the objective truth, and he therefore refused to tolerate alternative perspectives. This article subjects these claims to a textual analysis, and it argues that they are erroneous. Lenin defends a fallibilist account of science that affirms the uncertainty of knowledge in the natural, philosophical and social sciences. This fallibilism pervades the text that supposedly showcases his intolerance, Materialism and Empirio-Criticism. Lenin's scientific socialism opposes rigid conceptions of socialism, and it encourages an atmosphere of democratic debate. Whilst Lenin's writings have their flaws, they are not the founding documents of Marxist dogmatism that they are often portrayed as being. Lenin is not the narrow-minded vulgariser of Marxism that he is routinely taken to be.

'Strike out, right and left!': a conceptual-historical analysis of 1860s Russian nihilism and its notion of negation Abstract The aim of this essay is to synthesize as well as to analyze the conceptual evolution of 1860s Russian nihilism in general and its notion of negation in particular. The fictitious characters that traditionally have been informing the popular notion of "Russian nihilism" mainly refer to an antinihilistic genre. By analyzing nihilism also on the basis of primary sources, the antinihilistic notion of nihilism is nuanced, enabling a more comprehensive analysis of the movement's different aspects. In some instances, Russian nihilism has been taken out of context and portrayed as a monolith; its pursuit of "negation" interpreted literally. In this essay, a dialectical relation emerges, between affirmation and negation on the one hand as well as between the nihilist "children" and their idealist "fathers" on the other. Despite its radical stance, nihilism consists of a reconciliation of opposites. Although nihilists fought for autonomy, revolution and a new society, the movement was ironically stuck in a continuous negation of its inspirers and forerunners.

Literature and the revolution.

Note from the Editor in Chief

Die Vorahnung der Revolution in den Werken russischer Schriftsteller Abstract This article discusses the intellectual and spiritual atmosphere in Russia on the eve of the 1917 revolution. In particular, through the examples of Leo Tolstoy and Maxim Gorky, the author shows how the changes in the Russian economic and sociopolitical situation effected the intellectuals of the era. Despite the differences in social backgrounds, lifestyles, worldviews and artistic styles, Tolstoy's and Gorky's assessments of Russia's developmental prospects were in many ways consistent. As this article demonstrates, the values held by both writers were grounded in their unorthodox religious views. In conclusion, the author reexamines Lenin's assessment of both writers.

Theurgy revisited, or the harmony of cultural spheres Abstract The paper argues that Nikolai Berdyaev's doctrine of theurgy has remained relevant in today's cultural-historical context because it highlights a continuing problem in the philosophy of art. The problem is the misunderstanding of the ludic nature of art, its role in the evolution of consciousness and transformation of reality. The author questions the idea that artistic play is deficient compared with religious expression. As a result of this critique, he proposes that the theurgic quest for a radically new form of creativity was misguided and that the true meaning of the aspiration behind it is the need to comprehend culture as a dialectically articulated integral system of the cultural forms that constitute it.

A revolutionary as a "beautiful soul": Lev Tolstoy's path to ethical anarchism Abstract This article discusses Leo Tolstoy's view of the Russian revolutionary movement. Taking as a focal point the writer's lifelong interest in the Decembrist uprising of 1825 and particularly in the personalities of the gentry revolutionaries, the article argues that Tolstoy's fascination for these figures was due to their superior moral qualities, rather than to their political and socioeconomic doctrines. Following Alexander Herzen, Tolstoy came to regard the Decembrists as full-fledged individualities and "beautiful souls" (in Friedrich von Schiller's sense of the term). Thus, Tolstoy's much debated "conversion" and subsequent attempts to transform literary art into a medium of religious and moral reform (and thus a peaceful cultural revolution) can also be viewed as extensions of his project of self-understanding and self-formation according to the model of kalokagathia provided by Russia's aristocratic revolutionaries.

Revolutionen und Bohème. 1917–1918 Abstract This article analyzes the similarity of the revolutions of 1917–1918 with earlier revolutions in Russia and Germany. Several common characteristics are noted: "theatricality", the connection of politics with Bohemianism, and politics' concealed connection with art. The revolution presents a theatre stage on which representatives of the Boheme play their dreams (and nightmares) out in politics. Furthermore, the article investigates methodological pluralism, which constitutes the philosophical foundation of Bohemianism. Finally, the author distinguishes two types of Bohemian politicians: the first type, a "fantasist, dreamer, poet," is represented by Kurt Eisner, whereas the other type, that of a "multi-souled artist" is represented by Fyodor Stepun.

Preface

Correction to: The wound which will not close: Jan Patočka's philosophy and the conditions of politicization When the author wrote this article, he was working as part of the ERC project The Great War and Modern Philosophy. It has come to his attention that the article should have included the following acknowledgement:

Behavioral Health Services & Research

A History of Child and Adolescent Treatment Through a Distillation Lens: Looking Back to Move Forward Abstract Youth psychosocial treatments have proliferated over many decades and the time is ripe to examine the unique contribution of these treatments. Six hundred eighty-nine randomized clinical trials were examined from the PracticeWise Evidence-Based Services Database, an ongoing data source of youth psychosocial literature. A number of studies, treatment protocols, and practice elements across 11 youth problem areas (e.g., anxiety) from 1966 to 2016 are provided. Using distillation methodology, we compared the relationship between new treatment protocols and the identification of new practice elements within each problem area over time. Anxiety, disruptive behavior, attention/hyperactivity, and depression were the most studied problem areas, whereas suicide, eating disorders, and mania were least studied. While identification of new practice elements leveled off, studies continued to increase over time. For some problem areas, unique practice elements have not been identified for over a decade. Future studies examining treatment innovation and implications for behavioral health are discussed.

Evaluation of an Integrated Intensive Cognitive Behavioral Therapy Treatment Within Addiction Care Abstract The study aimed to evaluate an integrated intensive cognitive behavioral therapy (CBT) group treatment for people with substance-related syndrome in outpatient care and to identify eventual gender differences. The study population consisted of 35 outpatients (18 male, 17 female) at a clinic in Western Sweden. The patients completed a four-month period of intensive group therapy and participated in the data collection at admission and discharge. The data were collected using the following inventories: Beck Depression and Anxiety Inventories, Rosenberg Self-Esteem Scale, Hopelessness Scale, and Trait Hope Scale. Results showed decreases in anxiety, depression and experience of hopelessness, and increases in self-esteem and hope. In females, the most dramatic improvement was measured for the anxiety and depression attributes, while in males the strongest effect was measured for hope and self-esteem. This study provides clinical evidence of the positive effects of integrated intensive CBT in outpatient care of people with substance-related syndrome.

Assessing Social Connectedness Among Persons with Schizophrenia: Psychometric Evaluation of the Perceived Social Connectedness Scale Abstract The purpose of this study was a psychometric evaluation of the 4-item perceived social connectedness (PSC) scale. The study analyzed secondary data from a project that assessed physical, behavioral, and social health characteristics of adults with serious mental illness receiving integrated services at community mental health centers (CMHs). The current sample comprised those diagnosed with schizophrenia attending these CMHs (N = 146). Most participants were African-American males who receive disability benefits with Medicaid as health insurance. The sample self-reported low-to-moderate levels of social connectedness, daily functioning, and symptom severity. Factor analysis of the PSC scale revealed one dimension, accounting for 66% of total variance, with strong item loadings. Reliability coefficients indicated sufficient scale internal consistency. Construct validity was suggested via the PSC scale's directional, significant convergence with daily functioning and symptom severity. Implications include the application of the PSC scale for this socioeconomically disadvantaged population that customarily lacks meaningful social networks.

Reflecting on 15 Years Well Spent

Organizational Context and Individual Adaptability in Promoting Perceived Importance and Use of Best Practices for Substance Use Abstract This study examines associations among organizational context, staff attributes, perceived importance, and use of best practices among staff in community-based, juvenile justice (JJ) agencies. As part of the National Institute on Drug Abuse's Juvenile Justice—Translational Research on Interventions for Adolescents in the Legal System (JJ-TRIALS) study, 492 staff from 36 JJ agencies were surveyed about the perceived importance and use of best practices within their organization in five substance use practice domains: screening, assessment, standard referral, active referral, and treatment support. Structural equation models indicated that supervisory encouragement and organizational innovation/flexibility were associated with greater individual adaptability. Adaptability (willingness to try new ideas, use new procedures, adjust quickly to change), was positively correlated with importance ratings. Importance ratings were positively associated with reported use of best practices. Organizational climates that support innovation likely affect use of practices through staff attributes and perceptions of the importance of such services.

Utilization and Perceptions of Drop-in Center Services Among Youth Experiencing Homelessness Abstract Drop-in centers offer a range of services to assist unaccompanied youth experiencing homelessness, but little is known about their perceptions of drop-in centers or use of different services. A random sample of 273 youth experiencing homelessness in the Los Angeles area who had ever used a drop-in center was surveyed. Most youth heard about local drop-in centers from peers (65.1%). They generally reported positive perceptions of the drop-in center environment, staff, and clients; overall, 57.8% were "very" or "extremely" satisfied with the services they had received. Nearly all youth cited basic services (e.g., food, showers, clothes) as a reason they went to drop-in centers; far fewer reported going to obtain higher-level services (e.g., case management). Perceptions and utilization did not differ by sexual orientation; however, non-white youth were more likely than Whites to use drop-in centers for certain higher-level services. Strategies for engaging youth in drop-in center services are discussed.

Implementing Transdiagnostic Cognitive Behavioral Psychotherapy in Adult Public Behavioral Health: A Pilot Evaluation of the Feasibility of the Common Elements Treatment Approach (CETA) Abstract Few evidence-based psychotherapies are provided in adult public behavioral health (PBH), despite the need for such treatments. The common elements treatment approach (CETA) was developed for use by lay providers in low- and middle-income countries and may have relevance in PBH given its unique application with individuals with multiple diagnoses including PTSD, depression, and anxiety. This study utilized data collected as part of the implementation of CETA in 9 PBH agencies in Washington State with 58 providers, including a 2-day workshop and 6 months of consultation. Outcomes included provider-perceived skill in CETA delivery, training and consultation completion rates, and perceived appropriateness of CETA for clients. Thirty-nine (67%) providers completed requirements for training and consultation, and delivered CETA to a total of 56 clients. Perceived competence in delivering CETA improved over time, as well as client symptom scores. CETA shows promise for feasible and effective implementation within US-based PBH systems.

Overcoming Barriers to Adopting and Implementing Pharmacotherapy: the Medication Research Partnership Abstract Pharmacotherapy includes a growing number of clinically effective medications for substance use disorder, yet there are significant barriers to its adoption and implementation in routine clinical practice. The Medication Research Partnership (MRP) was a successful effort to promote adoption of pharmacotherapy for opioid and alcohol use disorders in nine substance abuse treatment centers and a commercial health plan. This qualitative analysis of interviews (n = 39) conducted with change leaders at baseline and at the end/beginning of 6-month change cycles explains how treatment centers overcame obstacles to the adoption, implementation, and sustainability of pharmacotherapy. Results show that barriers to adopting, implementing, and sustaining pharmacotherapy can be overcome through incremental testing of organizational change strategies, accompanied by expert coaching and a learning community of like-minded professionals. The greatest challenges lie in overcoming abstinence-only philosophies, establishing a business case for pharmacotherapy, and working with payers and pharmaceutical representatives.

Scratching the Surface of Psychiatric Services Distribution and Public Health: an Indiana Assessment Abstract Mental illness is a leading cause of disability with many public health implications. Previous studies have demonstrated a national shortage of psychiatrists, particularly in rural areas. An analysis of how this workforce distribution relates to population demographics and public/behavioral health is lacking in the literature. This study encompassed a statewide assessment of the Indiana psychiatric workforce as it relates to population characteristics and public/behavioral health. This study's findings demonstrate a profoundly low psychiatry workforce in rural counties of Indiana. The low psychiatry workforce capacity in rural counties is so disparate that the demographic and public/behavioral health characteristics differ from the State averages in the same manner as counties without a psychiatrist at all. The psychiatric workforce distribution did not differ significantly on the basis of poverty prevalence. The potential utility of indicators of population health was also evaluated and revealed that social factors such as poverty and Medicaid prevalence may be superior to more traditional measures.

Use of Guideline-Recommended Treatments for PTSD Among Community-Based Providers in Texas and Vermont: Implications for the Veterans Choice Program Abstract Implementation of the Veterans Choice Program (VCP) allows Veterans to receive care paid for by the Department of Veterans Affairs (VA) in community settings. However, the quality of that care is unknown, particularly for complex conditions such as posttraumatic stress disorder (PTSD). A cross-sectional survey was conducted of 668 community primary care and mental health providers in Texas and Vermont to describe use of guideline-recommended treatments (GRTs) for PTSD. Relatively, few providers reported using guideline-recommended psychotherapy or prescribing practices. More than half of psychotherapists reported the use of at least one guideline-recommended psychotherapy for PTSD, but fewer reported the use of core treatment components, prior training in the GRT(s) they use, or adherence to a treatment manual. Suboptimal prescribing for PTSD patients was reported more commonly than optimal prescribing. Findings raise critical questions regarding how to ensure veterans seeking PTSD care in community settings receive psychotherapy and/or prescribing consistent with clinical practice guidelines.

Follistatin-Like 1 Attenuates Ischemia/Reperfusion Injury in Cardiomyocytes via Regulation of Autophagy

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Background. The cardioprotective effect of FSTL1 has been extensively studied in recent years, but its role in myocardial ischemia/reperfusion injury (IRI) is unclear. In this study, we investigated the effect of FSTL1 pretreatment on myocardial IRI as well as the possible involvement of autophagic pathways in its effects. Methods. The effects of FSTL1 on the viability and apoptosis of rat cardiomyocytes were investigated after exposure of cardiomyocytes to hypoxia/ischemia by using the CCK-8 assay and Annexin V/PI staining. Further, western blot analysis was used to detect the effects of FSTL1 pretreatment on autophagy-associated proteins, and confocal microscopy was used to observe autophagic flux. To confirm the role of autophagy, the cells were treated with the autophagy promoter rapamycin or the autophagy inhibitor 3-methyladenine, and cell viability and apoptosis during IRI were observed. These effects were also observed after treatment with rapamycin or 3-methyladenine followed by FSTL1 administration and IRI. Results. FSTL1 pretreatment significantly increased viability and reduced apoptosis in cardiomyocytes exposed to hypoxia/ischemia conditions. Further, FSTL1 pretreatment affected the levels of the autophagy-related proteins and enhanced autophagic flux during IRI. In addition, cell viability was enhanced and apoptosis was decreased by rapamycin treatment, while these effects were reversed by 3-MA treatment. However, when the myocardial cells were pretreated with rapamycin or 3-methyladenine, there was no significant change in their viability or apoptosis with FSTL1 treatment during IRI. Conclusions. FSTL1 plays a protective role in myocardial IRI by regulating autophagy.

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A Concise Review of Pelvic Radiation Therapy (RT) for Rectal Cancer with Synchronous Liver Metastases

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Background and Objective. Colorectal cancer is a major health concern as a very common cancer and a leading cause of cancer-related mortality worldwide. The liver is a very common site of metastatic spread for colorectal cancers, and, while nearly half of the patients develop metastases during the course of their disease, synchronous liver metastases are detected in 15% to 25% of cases. There is no standardized treatment in this setting and no consensus exists on optimal sequencing of multimodality management for rectal cancer with synchronous liver metastases. Methods. Herein, we review the use of pelvic radiation therapy (RT) as part of potentially curative or palliative management of rectal cancer with synchronous liver metastases. Results. There is accumulating evidence on the utility of pelvic RT for facilitating subsequent surgery, improving local tumor control, and achieving palliation of symptoms in patients with stage IV rectal cancer. Introduction of superior imaging capabilities and contemporary RT approaches such as Intensity Modulated Radiation Therapy (IMRT) and Image Guided Radiation Therapy (IGRT) offer improved precision and toxicity profile of radiation delivery in the modern era. Conclusion. Even in the setting of stage IV rectal cancer with synchronous liver metastases, there may be potential for extended survival and cure by aggressive management of primary tumor and metastases in selected patients. Despite lack of consensus on sequencing of treatment modalities, pelvic RT may serve as a critical component of multidisciplinary management. Resectability of primary rectal tumor and liver metastases, patient preferences, comorbidities, symptomatology, and logistical issues should be thoroughly considered in decision making for optimal management of patients.

Oral Oncology

Impact of locoregional irradiation in patients with upfront metastatic head and neck squamous cell carcinoma Publication date: June 2019 Source: Oral Oncology, Volume 93 Author(s): A. Rambeau, V. Bastit, S. Thureau, J. Thariat, C. Moldovan, M. Roge, E. Babin, B. Gery, F. Di Fiore, C. Florescu, F. Clatot Abstract Objective To evaluate the frequency of use, modalities and potential interest of locoregional irradiation (LRT) in patients with upfront metastatic head and neck squamous cell carcinoma (HNSCC). Methods Retrospective multicentric study. Were included all patients presenting an upfront metastatic HNSCC treated by platin-5FU- cetuximab based regimen, from 2008 to 2016. Patients with past history of cervical irradiation or HNSCC within the 5 years before metastasis diagnosis were excluded. Results 65 patients were included. 25 patients (38%) presented a response or stable disease with chemotherapy. Forty-one patients (63%) underwent a locoregional irradiation: 5 patients before chemotherapy (upfront RT), 13 patients with stable disease or response after chemotherapy (consolidation RT), and 23 patients with progressive disease. Median overall survival (OS) was 11.6 months, median progression free survival was 7.9 months. OS was significantly improved for patients who underwent LRT (median OS 16.1 vs 7.5 months, p < 0.01). Among patients who received LRT, OS trended to be better if LRT was performed as consolidation RT compared to upfront RT (median OS of 22.1 vs 15.5 months, p = 0.11). Among patients with stable disease or response after chemotherapy, there was a non-significant better OS for the 13 patients treated by LRT (median OS 22.1 vs 11.8 months, p = 0.21)). Radical dose was not associated with better locoregional control compared to palliative dose (p = 0.37). Conclusion LRT is frequently performed during management of upfront metastatic HNSCC and associated with better OS. Non-progressive disease after firs-line chemotherapy seems a good way to select patients who would benefit from radical LRT.

Concurrent chemoradiotherapy with nedaplatin versus cisplatin in stage II-IVB nasopharyngeal carcinoma: A cost-effectiveness analysis Publication date: June 2019 Source: Oral Oncology, Volume 93 Author(s): Weiting Liao, Jiaxing Huang, Qiuji Wu, Guiqi Zhu, Xinyuan Wang, Feng Wen, Pengfei Zhang, Nan Zhang, Qiu Li Abstract Background Nedaplatin-based concurrent chemoradiotherapy became an alternative doublet treatment strategy to cisplatin-based concurrent chemoradiotherapy in patients with locoregional, advanced nasopharyngeal carcinoma. Materials and methods Using a Markov model, we simulated patients with nasopharyngeal carcinoma from disease-free to death. Input data for the model were collected from published literature and the standard fee database of West China Hospital. The outcome was expressed in quality-adjusted-years (QALYs), net monetary benefit at the threshold of $25,841, three times the Gross Domestic Product of China in 2017. The costs and benefits were discounted at 3% annually and a half-cycle correction was considered. The input parameters were varied in one-way sensitivity analysis to confirm the robustness of the model. All of the primary analyses used second-order probabilistic sensitivity analysis to capture the impact of parameter uncertainty based on 10,000 Monte-Carlo simulations. Results The mean QALYs of treatment in stage II-IVB nasopharyngeal carcinoma were comparable: 2.90 QALYs for nedaplatin and 3.12 QALYs for cisplatin. Nedaplatin cost $34,505 compared with $27,167 for cisplatin, generating an incremental net monetary benefit of nedaplatin versus cisplatin of $-13,357 at the ceiling ratio of $25,841. The results of nedaplatin remained cost-ineffective over the majority of the sensitivity analyses. The cost-effectiveness curve showed that the probability of strategies being cost-effective were 0% for nedaplatin and 100% for cisplatin in stage II-IVB nasopharyngeal carcinoma at any willingness-to-pay threshold. Conclusions Nedaplatin is a dominated, cost-ineffective alternative to concurrent chemoradiotherapy in stage II-IVB nasopharyngeal carcinoma compared with cisplatin from the perspective of Chinese society.

Altered-fractionation radiotherapy improves local control in early-stage glottic carcinoma: A systematic review and meta-analysis of 1762 patients Publication date: June 2019 Source: Oral Oncology, Volume 93 Author(s): Lucas Gomes Sapienza, Matthew Stephen Ning, Senzo Taguchi, Vinícius Fernando Calsavara, Antônio Cássio de Assis Pellizzon, Maria José Leite Gomes, Luiz Paulo Kowalski, Glauco Baiocchi Abstract Objectives To perform a systematic review of 1762 patients to comprehensively assess the benefit of altered-fractionation radiotherapy (ART) in early stage glottic carcinoma (ESGC). Materials and methods Studies were identified in PubMed and EMBASE. Inclusion criteria were: (1) diagnosis of squamous cell ESGC (Tis, T1, T2); (2) ART versus conventionally-fractionationated radiotherapy (CRT); and (3) provision of number of local recurrence events and total numbers per fractionation arm. The random-effects model was fitted to estimate the pooled hazard ratio (HR). Subgroup sensitivity analyses were performed based on ART strategy (hypo- versus hyperfractionation), treatment-day reductions, machine type, tumor stage, and anterior commissure involvement. Results Eleven studies met inclusion criteria: 4 randomized controlled trials (RCTs) and 7 two-arm retrospective studies. ART was associated with 38% fewer (HR 0.62; 95% CI: 0.46–0.82, p = 0.0009) and 60% fewer (HR 0.40; 95% CI: 0.24–0.66, p = 0.0003) local failure events in pooled analyses of the RCTs and retrospective studies, respectively. Both hyperfractionation (HR 0.65; 95% CI: 0.43–0.97, p = 0.03) and hypofractionation (HR 0.55; 95% CI: 0.33–0.91, p = 0.02) strategies were superior to CRT. The benefit persisted for all treatment- and tumor-related parameters, including anterior commissure involvement, with the exception of a pooled analysis of studies with predominantly T2 (<50% T1) cases (HR 0.60, 95% CI: 0.30–1.20, p = 0.15). Conclusion Both hypofractionation and hyperfractionation improve local control in ESGC, including T1 tumors and for anterior commissure involvement. However, this benefit may not persist for T2 tumors, for which alternative strategies should be considered.

Clinical outcome of stereotactic body radiotherapy for lung-only oligometastatic head and neck squamous cell carcinoma: Is the deferral of systemic therapy a potential goal? Publication date: June 2019 Source: Oral Oncology, Volume 93 Author(s): Pierluigi Bonomo, Daniela Greto, Isacco Desideri, Mauro Loi, Vanessa Di Cataldo, Ester Orlandi, Nicola Alessandro Iacovelli, Carlotta Becherini, Luca Visani, Viola Salvestrini, Matteo Mariotti, Lorenzo Livi Abstract Objectives Oligometastatic head and neck squamous cell carcinoma (HNSCC) is a rare entity with no evidence-based treatment recommendations available to support the use of local ablative therapies. The aim of our study was to report on the clinical benefit of stereotactic body radiotherapy (SBRT) for patients with lung-only oligometastases, defined by the presence of 1 to 5 pulmonary lesions. Material and Methods SBRT was applied in case of single lesions deemed amenable to local treatment only ("de novo" pattern) or after first line chemotherapy at time of disease oligoprogression ("induced" pattern). To assess the potential deferral of systemic therapy in both time points, we analyzed time to progression (TTP) defined as the time from the last day of SBRT to disease progression or death from any cause. Cox regression analysis was performed to identify predictive factors of better outcome. Results Twenty-seven patients were retrospectively evaluated. The majority (81.5%) had HPV negative disease and a "de novo" oligometastatic pattern (78.6%). The median maximum lesion diameter and target size were 1.5 cm and 22.7 cc, respectively. At a median follow-up of 22 months (range 6–73), the median TTP was 10 months (95% CI: 9.5–21.1), with 1- and 2-year rates of 56.2% and 35%, respectively. The objective response rate at 3 months after SBRT was 75%. At multivariate analysis baseline T3/T4 stage had a HR for worse outcome of 5.38 (p = 0.033). Acute toxicity was minimal (G1/G2 of 14.8%). Conclusion In properly selected oligometastatic patients, SBRT has potential for sustained deferral of systemic treatment.

Assessment of oral health-related quality of life instruments for oral submucous fibrosis: A systematic review using the COnsensus-based Standards for the selection of health Measurement Instruments (COSMIN) checklist Publication date: June 2019 Source: Oral Oncology, Volume 93 Author(s): Shailesh M. Gondivkar, Rahul R. Bhowate, Amol R. Gadbail, Sachin C. Sarode, Rima S. Gondivkar Abstract Quality of life (QoL) instruments are becoming increasingly important in research and often used in clinical practice. Various QoL instruments have been developed/ validated for assessment of oral health-related QoL (OHRQoL) in patients with oral submucous fibrosis (OSF). Selection of an adequate instrument is challenging in routine practice due to lack of information on psychometric quality of measurement instruments. This systematic review gives an extensive overview of quality of all the currently available measurement instruments for use in OSF patients. PubMed, Scopus, Web of Science and CINAHL were searched for relevant literature until December 2018 and the information was extracted according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. The quality of the identified studies was assessed per measurement property according to the COnsensus-based Standards for the selection of health Measurements Instruments (COSMIN) checklist. Four studies that met the inclusion criteria were included. Three generic and one disease-specific QoL instruments were identified. Information regarding important measurement properties was often incomplete. The evidence for the quality of measurement instruments was found to be variable, none of the instruments performed sufficient on all measurement properties. Based on the available information, OHRQoL-OSF appeared to have adequate COSMIN measurement properties. As recently published, newer QoL instruments have not yet been evaluated in an adequate manner for use in OSF. We suggest future studies should implement OSF-specific OHRQoL-OSF to better understand OSF patients' perspectives and help inform clinicians to propose treatment strategies as per patients' needs.

Tumor safety and side effects of photobiomodulation therapy used for prevention and management of cancer treatment toxicities. A systematic review Publication date: June 2019 Source: Oral Oncology, Volume 93 Author(s): Mariana de Pauli Paglioni, Anna Luíza Damaceno Araújo, Lady Paola Aristizábal Arboleda, Natalia Rangel Palmier, Jéssica Montenegro Fonsêca, Wagner Gomes-Silva, Cristhian Camilo Madrid-Troconis, Felipe Martins Silveira, Manoela Domingues Martins, Karina Morais Faria, Ana Carolina Prado Ribeiro, Thaís Bianca Brandão, Marcio Ajudarte Lopes, Adriana Franco Paes Leme, César Augusto Migliorati, Alan Roger Santos-Silva Abstract Photobiomodulation therapy (PBMT), also known as low-level laser therapy (LLLT), has been increasingly used for the treatment of toxicities related to cancer treatment. One of the challenges for the universal acceptance of PBMT use in cancer patients is whether or not there is a potential for the light to stimulate the growth of residual malignant cells that evaded oncologic treatment, increasing the risk for tumor recurrences and development of a second primary tumor. Current science suggests promising effects of PBMT in the prevention and treatment of breast cancer-related lymphedema and oral mucositis, among other cancer treatment toxicities. Nevertheless, this seems to be the first systematic review to analyze the safety of the use of PBMT for the management of cancer-related toxicities. Scopus, MEDLINE/PubMed, and Embase were searched electronically. A total of 27 articles met the search criteria. Selected studies included the use of PBMT for prevention and treatment of oral mucositis, lymphedema, radiodermatitis, and peripheral neuropathy. Most studies showed that no side effects were observed with the use of PBMT. The results of this systematic review, based on current literature, suggest that the use of PBMT in the prevention and management of cancer treatment toxicities does not lead to the development of tumor safety issues.

Endoscopic-assisted maxillectomy: Operative technique and control of surgical margins Publication date: June 2019 Source: Oral Oncology, Volume 93 Author(s): Alberto Deganello, Marco Ferrari, Alberto Paderno, Mario Turri-Zanoni, Alberto Schreiber, Davide Mattavelli, Alperen Vural, Vittorio Rampinelli, Alberto Daniele Arosio, Alessandro Ioppi, Mario Cherubino, Paolo Castelnuovo, Piero Nicolai, Paolo Battaglia Abstract Background When amenable to radical excision, cancer involving the maxilla is typically treated with maxillectomy followed by adjuvant therapy. Posterior tumor extension beyond the maxillary box leads to the invasion of complex areas, where achieving clear margins may be challenging. Methods Patients undergoing endoscopic-assisted maxillectomy for nasoethmoidal, maxillary, or hard palate cancer between 2007 and 2017 were included in the study. Surgical technique, margin status, and recurrences were analyzed. Extension of posterior resection was classified in 3 types (type 1: resection of the pterygopalatine fossa; type 2: resection of the pterygoid plates and related muscles; type 3: resection of the upper parapharyngeal space). The analysis of putative risk factors for involvement of margins and local recurrence was performed with special focus on the posterior and medial margin. Results The study included 79 patients (75 with available follow-up; mean: 20.6 months, range: 6–101 months), 37 (46.8%) of whom underwent type 1 resection, 34 (43.0%) type 2, and 8 (10.1%) type 3. According to pT category, 57 (72.2%) tumors were classified as T4a/T4b. Posterior and medial clear margins were achieved in 76/79 (96.2%) and 75/79 (94.9%) patients, respectively. T4b category, extension to the ethmoid, sphenoid sinus, pterygoid process, orbital cavity, and premaxillary tissues were significantly associated with a higher rate of margin involvement. None of the factors was significantly associated with medial margin involvement. Conclusion Endoscopic-assisted maxillectomy combines several refinements including the facilitated detachment of the maxilla from the skull base and precise delineation of the posterior and medial margins of resection.

Prognostic implications of pathologic lymph nodes in HPV-positive oropharyngeal cancers: Clinical validity and strategies for routine clinical practice Publication date: May 2019 Source: Oral Oncology, Volume 92 Author(s): Rama Jayaraj, Chellan Kumarasamy, Madhav Madurantakam Royam, Shanthi Sabarimurugan, Siddhartha Baxi

Ossified Carcinoma Ex Pleomorphic Adenoma in accessory lobe of parotid gland: Complexity in clinical, imaging and histologic diagnosis and minimally invasive surgery Publication date: May 2019 Source: Oral Oncology, Volume 92 Author(s): Raffaele Rauso, Giuseppe Colella, Renato Franco, Andrea Ronchi, Fabrizio Chirico Abstract Carcinoma ex pleomorphic adenoma is not common among malignant salivary tumors and an accessory lobe of parotid gland tumor with a carcinoma ex pleomorphic adenoma histology is even rarer. Management of these tumors include a high index of suspicion, good understanding of the anatomy and a meticulous surgical access. The exceptional localization of an ossified Carcinoma ex Pleomorphic Adenoma in the accessory lobe of the parotid gland, never reported to date in the literature, has prompted us to report this case to stress the challenging difficulties related to clinical and histologic diagnosis and to analyze a minimally invasive intraoral approach.

Revisiting and revising the definition of oral submucous fibrosis Publication date: May 2019 Source: Oral Oncology, Volume 92 Author(s): Mohit Sharma, Raghu Radhakrishnan

Cancer Treatment Reviews

Emerging therapeutic targets for patients with advanced prostate cancer Publication date: June 2019 Source: Cancer Treatment Reviews, Volume 76 Author(s): Fred Saad, Neal Shore, Tian Zhang, Shikhar Sharma, Helen K. Cho, Ira A. Jacobs Abstract Although recent advances in the treatment of castration-resistant prostate cancer (CRPC) have significantly improved patient outcomes, advanced prostate cancer is still associated with substantial morbidity and mortality, particularly in patients who develop resistance after multiple lines of therapy. Various cell signaling, DNA repair, and epigenetic enzymatic pathways are being targeted with small-molecule inhibitors in order to identify treatment strategies for patients with CRPC. In this review, we discuss novel targets and agents, studied preclinically and now being validated in clinical trials, including poly ADP-ribose polymerase (PARP), enhancer of zeste homologue 2 (EZH2), hedgehog pathway, MDM2/p53, and tyrosine kinase inhibitors. Further, we outline current approaches for novel prostate cancer vaccines such as DCVAC/PCa, PROSTVAC-V/F, MVI-816, CV9104, and PF-06753512. This wide spectrum of potential treatment strategies holds promise for additional improvements in the treatment of patients with CRPC, as these novel agents are aimed at targets known to be associated with growth and malignant progression of prostate cancer. If primary study endpoints are met, findings from ongoing phase III trials of well-tolerated and active combinations may provide new effective treatment options for advanced prostate cancer and thereby contribute to enhanced disease control in CRPC patients.

Genomic profiling in pancreatic ductal adenocarcinoma and a pathway towards therapy individualization: A scoping review Publication date: May 2019 Source: Cancer Treatment Reviews, Volume 75 Author(s): Ritu R. Singh, Johanna Goldberg, Anna M. Varghese, Kenneth H. Yu, Wungki Park, Eileen M. O'Reilly Abstract Context Pancreatic cancer (PDAC) is one of the most challenging cancers to treat with modest recent improvements in survival from new systemic therapies. There is growing interest in individualized therapy underpinned by somatic and germline genomic alterations. Objective A systematic review of data on therapies targeting somatic and germline alterations, and their downstream pathways in PDAC. Method A systematic literature search was conducted using PRISMA guidelines to include relevant results published after January 1, 2008. Results A total of 71 relevant studies were included. We identified 36 studies targeting the KRAS-pathway, the most common being with MEK-inhibitor therapy. Twenty-two studies were identified that evaluated platinum-based chemotherapy and PARP inhibitors in patients with deleterious mutations in DNA damage repair genes and have shown encouraging results. Immunotherapy has demonstrated activity in patients with mismatch repair deficiency/microsatellite instability. Conclusion Evidence from translational and clinical research presents an exciting platform for genomic targeted therapy in PDAC. Validity for targeting BRCA with platinum and PARP inhibitors and microsatellite instability with immune therapy has been established, nonetheless, evidence for targeting the common driver oncogenes is lacking and much work is needed. Of importance is identifying the subgroup of KRAS -wild type PDAC (approximately 5%) where there is enrichment for targetable opportunities.

Short-duration versus 1-year adjuvant trastuzumab in early HER2 positive breast cancer: A meta-analysis of randomized controlled trials Publication date: May 2019 Source: Cancer Treatment Reviews, Volume 75 Author(s): Lujia Chen, Wenqi Zhou, Xiaolei Hu, Man Yi, Changsheng Ye, Guangyu Yao Abstract Background One year of adjuvant trastuzumab treatment is the standard of care for early stage human epidermal growth factor receptor 2 (HER2)-positive breast cancer patients; however, controversy remains regarding the optimal schedule of trastuzumab because the selection of the 1-year schedule was arbitrary. After the remarkable results of the PERSEPHONE trial as well as the updated final results of the PHARE trial, we performed an updated meta-analysis to reassess the efficacy and safety of shorter durations of trastuzumab. Methods A literature search of databases was conducted to identify randomized controlled trials reporting the efficacy and cardiotoxicity of shorter-duration and standard 1-year trastuzumab treatment. The hazard ratios (HRs) of disease-free survival (DFS) and overall survival (OS), and the odds ratios (ORs) of cardiac events were also estimated and pooled. Results Six studies were eligible, including a total of 11,496 patients. Both DFS (HR = 1.13; 95% confidence interval [CI] = 1.03–1.25; p = 0.01) and OS (HR = 1.16; 95% CI = 1.01–1.32; p = 0.03) were significantly improved with conventional 1-year trastuzumab treatment compared with shorter treatments. The more pronounced survival benefits observed in patients with negative estrogen receptor (ER) tumor and nodal involvement should be interpreted cautiously because of the lack of interaction between the survival benefit and ER, as well as the nodal status (interaction test, ER status: p = 0.26; nodal status: p = 0.60). One year of trastuzumab treatment resulted in a substantial DFS benefit compared with shorter schedules when administered concurrently with chemotherapy (HR = 1.22; 95% CI = 1.09–1.38; p = 0.0008; p = 0.02 for the interaction test). Patients in the shorter duration group experienced significantly fewer cardiac events (OR = 0.52; 95% CI = 0.43–0.62; p < 0.00001). Conclusions Though correlated with an increasing risk of cardiotoxicity, 1 year of adjuvant trastuzumab treatment conferred substantial survival benefits and should remain as the preferred treatment for early stage HER2-positive breast cancer. Shorter durations of trastuzumab may serve as an alternative choice for patients with cardiac disease and those at lower risk of recurrence.

Personalizing therapy for older adults with acute myeloid leukemia: Role of geriatric assessment and genetic profiling Publication date: May 2019 Source: Cancer Treatment Reviews, Volume 75 Author(s): Vijaya Raj Bhatt Abstract Acute myeloid leukemia (AML) presents therapeutic challenges in older adults because of high-risk leukemia biology conferring chemoresistance, and poor functional status resulting in increased therapy-related toxicities. Recent FDA approval of 8 new drugs for AML has increased therapeutic armamentarium and also provides effective low-intensity treatment options. Rational therapy selection strategies that consider individual's risk of therapy-related toxicities and probability of disease control can maximize benefits of available treatments. Studies have demonstrated that fitness level, measured by geriatric assessment can predict therapy-related toxicities, whereas cytogenetic and mutation results correlate with the probability of responses to standard chemotherapy. We are approaching an era when we move from "one size fits all" approach to personalized therapy selection based on geriatric assessment, genetic and molecular profiling.

Aggressive variants of prostate cancer – Are we ready to apply specific treatment right now? Publication date: May 2019 Source: Cancer Treatment Reviews, Volume 75 Author(s): Igor Tsaur, Isabel Heidegger, Alexander Kretschmer, Hendrik Borgmann, Giorgio Gandaglia, Alberto Briganti, Pieter de Visschere, Romain Mathieu, Massimo Valerio, Roderick van den Bergh, Piet Ost, Cristian Mirvald, Derya Tilki, Guillaume Ploussard, Cristian Surcel, On behalf of the EAU-YAU Prostate Cancer Working Party Abstract Recently, adoption of novel drugs for systemic treatment of metastatic prostate cancer has led to a striking improvement of response rate and survival in both hormone-sensitive and castration-resistant disease. In most cases, prostate cancer essentially depends on androgen receptor signaling axis, even in castration-resistant setting, and hence may be targeted by second generation hormonal therapy. However, a subset of patients bears androgen-independent cancer biology with a short-term response to hormonal treatment, early and extensive visceral metastases, low PSA levels and poor outcomes. Identification and specific management of these rapidly fatal malignancies is of an unmet medical need since their classification and utilized therapeutic regimens vary significantly. Unfortunately, molecular pathways have not been sufficiently elucidated yet in order to provide an effective targeted treatment with a prolonged response. Lack of diagnostic and predictive biomarkers for these cancers makes successful counteractions against them even more sophisticated. In this comprehensive review, we aimed at summarizing the current body of literature reporting on causal molecular machinery as well as diagnostic and therapeutic concepts of aggressive prostate tumors and draw clinically relevant conclusions for the up-to-date sensible disease management.

Refining adjuvant therapy for non-metastatic colon cancer, new standards and perspectives Publication date: May 2019 Source: Cancer Treatment Reviews, Volume 75 Author(s): Julien Taieb, Thierry André, Edouard Auclin Abstract Colon cancer is the third most frequent cancer in males and the second in females. Approximately 75% are diagnosed at a localized stage. Recurrence occurs in 30% of patients when there is nodal involvement (stage III) due to micrometastatic spreading. To date only chemotherapeutic drugs such as fluoropyrimidines or oxaliplatin have proven effective to kill this residual disease and are currently recommended by scientific societies. To improve patient management in the near future, recent research has focused on new ways of using currently available agents, tools to better define each individual patient prognosis more clearly so as to tailor adjuvant treatment, and molecular profiling to identify specific subgroups of patients with tumors that may benefit from specific therapeutic approaches. In this review, we will focus on current scientific knowledge on adjuvant treatment in localized colon cancer, the duration and timing of adjuvant therapy and the perspectives for better selection of patients who will benefit from adjuvant treatments.

Choosing wisely first line immunotherapy in non-small cell lung cancer (NSCLC): what to add and what to leave out Publication date: May 2019 Source: Cancer Treatment Reviews, Volume 75 Author(s): C. Proto, R. Ferrara, D. Signorelli, G. Lo Russo, G. Galli, M. Imbimbo, A. Prelaj, N. Zilembo, M. Ganzinelli, L.M. Pallavicini, I. De Simone, M.P. Colombo, A. Sica, V. Torri, M.C. Garassino Abstract Immunotherapy has dramatically changed the therapeutic scenario in treatment naïve advanced non-small cell lung cancer (NSCLC). While single agent pembrolizumab has become the standard therapy in patients with PD-L1 expression on tumor cells ≥ 50%, the combination of pembrolizumab or atezolizumab and platinum-based chemotherapy has emerged as an effective first line treatment regardless of PD-L1 expression both in squamous and non-squamous NSCLC without oncogenic drivers. Furthermore, double immune checkpoint inhibition has shown promising results in treatment naïve patients with high tumor mutational burden (TMB). Of note, the presence of both negative PD-L1 expression and low TMB may identify a subgroup of patients who has little benefit from immunotherapy combinations and for whom the best treatment option may still be platinum-based chemotherapy. To date, first-line single agent immune checkpoint blockade has demonstrated limited activity in EGFR mutated NSCLC and the combination of immunotherapy and targeted agents has raised safety concerns in both EGFR and ALK positive NSCLC patients. Finally, in EGFR mutated or ALK rearranged NSCLC, atezolizumab in combination with platinum-based chemotherapy and bevacizumab is emerging as a potential treatment option upon progression to first line tyrosine kinase inhibitors.

Editorial Board Publication date: May 2019 Source: Cancer Treatment Reviews, Volume 75 Author(s):

Management of metastatic bladder cancer Publication date: Available online 15 April 2019 Source: Cancer Treatment Reviews Author(s): Rosa Nadal, Joaquim Bellmunt Abstract Important advances in the understanding of the biology and mechanisms of tumor progression of urothelial carcinoma (UC) have been achieved over the past decade. The treatment landscape for advanced-stage, unresectable or metastatic UC has shifted dramatically over a short period of time, with 5 new therapeutic agents available for clinical use. The use of traditional chemotherapy and new immune checkpoints inhibitors (ICIs) directed at programmed cell-death protein 1 (PD-1) or its ligand has led to unprecedented survival benefits in selected patients with metastatic UC. Data show that anti-PD-1 ICIs are not only improving long-term clinical benefit, but also quality of life for patients in the second-line setting. In the front-line setting, regulatory agencies have restricted the indications of atezolizumab and pembrolizumab (both ICIs) to patients with PD-L1positivity with advanced UC and who are platinum-ineligible. Meanwhile, erdafitinib, a pan-FGFR inhibitor, and enfortumab vedotin, an antibody-drug conjugate, have been granted breakthrough designation by the FDA for the treatment of metastatic UC. Here we review the clinical trial data that have established standard-of-care treatment for advanced-stage UC. In addition, mechanisms of resistance and biomarkers of response to platinum-based chemotherapies and immunotherapies are also discussed, along with the clinical benefits and limitations of these therapies.

Cell and Tissue Banking

Effect of antibiotic impregnation time on the release of gentamicin from cryopreserved allograft bone chips: an in vitro study Abstract Freezing is the most common method for storing bones until use in skeletal reconstruction. However, the effect of freezing at different temperatures on antibiotic delivery from antibiotic-coated bone chips has not been evaluated. In this study, we compared antibiotic delivery in vitro from gentamicin-coated human bone stored at different temperatures impregnated for different time periods. Bone chips obtained from human femur heads were chemically cleaned and mixed with gentamicin sulfate solution for 1 h and 10 h respectively. Samples of both groups were cryopreserved for 4 months at − 20 °C, 4 months at − 80 °C, or evaluated immediately without freezing. Antibiotic release from the bone chips was measured using Bacillus subtilis as an indicator strain. Zones of inhibition and rates of gentamicin were higher for the samples impregnated for 10 h as compared to 1 h. There was no significant difference between non-cryopreservation, cryopreservation at different temperatures of − 20 and − 80 °C on the release of gentamicin from bone chips even after storage for 4 months.

Correction to: Defined serum- and xeno-free cryopreservation of mesenchymal stem cells In the original article, Fig. 1A was by mistakenly duplicated. The corrected image is provided in this correction article.

Comparative evaluation of bioburden and sterility of indigenously prepared bone allograft with and without gentamicin Abstract During bone allograft processing, despite stringent donor screening and use of aseptic techniques, microbial invasion may occur due to the porous nature of the graft and cause potentially fatal infections. The aim of the present study was to prepare bone allograft with and without gentamicin and to compare bioburden and sterility in the obtained grafts to evaluate the role of antibiotic in enhancing graft safety. Fifty samples of demineralized freeze-dried bone allograft were prepared from suitable donors according to international standards. Randomly selected 25 samples were placed in 8 mg gentamicin/gram bone solution for 1 h. Packaging and sealing was done to ensure no microbial ingress during transportation. 40 samples were selected for bioburden testing. Remaining 10 were subjected to 25 kGy gamma radiation and tested for sterility. Microbiological evaluation revealed no evidence of colony forming units in all the samples of both the groups (Bioburden = 0). Post-radiation sterility testing also revealed no bacterial colony in the tested samples from both the groups. Favorable results validate the processing protocol while comparable results in both groups indicate no additive benefit of gentamicin addition. Nil bioburden may be used in further studies to determine a lower radiation dose to achieve adequate sterility and minimize the disadvantages of radiation like collagen cross-linking and decreased osteoinductive capacity.

Quality assessment on the long-term cryopreservation and nucleic acids extraction processes implemented in the andalusian public biobank Abstract Human samples are commonly collected and long-term stored in biobanks for current and future analyses. Even though techniques for freezing human blood are well established, the storage time can compromise the cell viability as well as the yield and quality of nucleic acids (RNA and DNA) extracted from them. In this study, a protocol to obtain peripheral blood mononuclear cells (PBMCs) from 70 subjects, which were stored at − 196 °C from EDTA tubes for a long-term, was assessed. In parallel; a protocol to obtain DNA from the same subjects, which were stored at − 80 °C from citrate tubes, was also studied. Samples stored from 2008 to 2012 were studied and the results obtained showed that there were no statistically significant differences in the RNA or DNA extracted in terms of purity, integrity and functionality The freezing protocol used by the Málaga Biobank shows that viable PBMCs and DNA could be kept for a period of, at least, 10 years, with a high quality and performance. Furthermore, RNA extracted from these PBMCs presents also a good quality and performance. Therefore, the samples frozen according to the conditions of the protocols assessed in this study could be optimal for biomedical research.

Mechanical and structural properties of human aortic and pulmonary allografts do not deteriorate in the first 10 years of cryopreservation and storage in nitrogen Abstract The aortic and pulmonary allograft heart valves (AHV) are used in the cardiac surgery for replacing the impaired semilunar valves. They are harvested from donor hearts and cryostored in tissue banks. The expiration period was set to 5 years arbitrarily. We hypothesized that their mechanical and structural properties do not deteriorate after this period. A total of 64 human AHV (31 aortic and 33 pulmonary) of different length of cryopreservation (fresh, 0–5, 5–10, over 10 years) were sampled to different tissue strips (artery, leaflet, ventriculo-arterial junction) and tested by tensile test with loading velocity 10 mm/min until tissue rupture. Neighbouring regions of tissue were processed histologically and evaluated for elastin and collagen area fraction. The results were evaluated statistically. In aortic AHV, the physical deformation response of wall samples to stress did not changed significantly neither during the process of cryopreservation nor during the first 10 years of storage. In pulmonary AHV, the ultimate strain dropped after 5 years of cryopreservation indicating that pulmonary artery was significantly less deformable at the time of rupture. On the other hand, the ultimate stress was equal during the first 10 years of cryostorage. The changes in collagen and elastin amount in the tissue samples were not associated with mechanical impairment. Neither elasticity, stiffness and solidity nor morphology of aortic and pulmonary AHV did not change reasonably with cryopreservation and in the first 10 years of cryostorage. This evidence suggests that the expiration period might be extended in the future.

A protocol for isolation and identification and comparative characterization of primary osteoblasts from mouse and rat calvaria Abstract Calvaria from neonatal mouse and rat is ideal resource for osteoblasts but can be easily contaminated by other cells such as fibroblasts. Here, we established a protocol for isolation and purification of primary osteoblast by enzyme sequential digestion and differential adhesion. In addition, we compared the phenotypic and functional traits of osteoblasts from mouse and rat which are commonly employed in studies. The method applied equally to rat and mouse in osteoblasts isolation and was corroborated its feasibility and validity. The results also provided us evidences for other experiments such as choosing a certain time point to give intervention and do the relevant tests.

Integration of C-type natriuretic peptide gene-modified bone marrow mesenchymal stem cells with chitosan/silk fibroin scaffolds as a promising strategy for articular cartilage regeneration Abstract The treatment of articular cartilage defects has become a major clinical concern. Currently, additional efforts are necessary to develop effective methods to cure this disease. In this work, we combined gene therapy with tissue engineering methods to test their effect on cartilage repair. In in vitro experiments, we obtained C-type natriuretic peptide (CNP) gene-modified bone marrow-derived mesenchymal stem cells (BMSCs) by transfection with recombinant adenovirus containing the CNP gene and revealed that CNP gene-modified BMSCs had good chondrogenic differentiation ability. By the freeze-drying method, we successfully synthesized a chitosan/silk fibroin (CS/SF) porous scaffold, which had a suitable aperture size for chondrogenesis. Then, we loaded CNP gene-modified BMSCs onto CS/SF scaffolds and tested their effect on repairing full-thickness cartilage defects in rat joints. The gross morphology and histology examination results showed that the composite of the CNP gene-modified BMSCs and CS/SF scaffolds had better repair effects than those of the other three groups at each time point. Additionally, compared to the group with BMSCs and scaffolds, we found that there was more cartilage matrix in the CNP gene-modified BMSCs and CS/SF scaffolds group. Data obtained in the present study suggest that the composite of CNP gene-modified BMSCs and CS/SF scaffolds represent promising strategies for repairing focal cartilage lesions.

Adipose-derived mesenchymal stem cell exosomes: a novel pathway for tissues repair Abstract The well-characterized curative effect of transplanted mesenchymal stem cells has been mainly attributed to their homing and subsequent differentiation for the repair and regeneration of damaged tissue. Adipose-derived mesenchymal stem cells (ADMSCs) are not only multipotent and plastic, but also abundant as they can be easily harvested with minimally invasive surgical techniques. This makes ADMSCs conducive for clinical applications. Recently, the secretory function of ADMSCs has been regarded as the primary mediator of MSC-based therapy. Exosomes are one kind of small cell extracellular membrane vesicles, which are primarily used to deliver cell-specific proteins, as well as nucleic acids secreted by various cell types. This review will introduce and characterize exosomes-derived ADMSCs (ADMSCs-Exo) and look at new therapies and prospective, including the limitations and outlook for therapeutic strategy. We will describe the latest research progress on myocardial repair, neuroprotection and neurotrophic effects, hepatic repair, renal repair, cutaneous repair, regeneration and other aspects using these cells.

Encapsulated explant in novel low shear perfusion bioreactor improve cell isolation, expansion and colony forming unit Abstract One of most important issue in the field of regenerative medicine is selection of appropriate cells, scaffolds and bioreactors. The present study aimed to investigate the appropriate method for the isolation of human UC-MSCs cells from explant cultured in alginate scaffold within novel perfusion bioreactor. MSCs were isolated with explant method and CD markers such CD73, CD31, CD90 and CD105 as were analyzed by flow cytometry. The culture chamber of the novel perfusion bioreactor was made from Plexiglas and housed the cell/scaffold constructs in the central part and the medium for the whole culture period. The flow behavior within the bioreactor chamber were performed for closed and open bypass systems. The shear stress profiles simulated using CFD modeling. The fluid flow distribution within the bioreactor chamber was performed in PBS solution containing a blue colorant. UC explants were resuspended in sodium alginate and were allowed to polymerize and placed in the perfusion bioreactor and cultured. MSCs were positive for mesenchymal markers such as CD73 and CD31. All 3D Perfusion bioreactor parts, except peristaltic pump was sterilizable by autoclaving. Results of CFD indicated very low wall shear stress on surface of culture chamber at flow rate 2 ml/min. The maximum wall shear stress was 1.10 × 10−3 m/s = 0.0110 dyne/cm2 (1 Pa = 10 dyne/cm2). The fluid flow distribution within the alginate gel initially exhibited oscillation. In comparison, when encapsulated explants were placed in the perfusion bioreactor, cell proliferation appeared faster (4.6 × 1011 ± 9.2 × 1011) than explants cultures in 2D conventional culture method (3.2 × 1011 ± 1 × 1011). Proliferated cell formed several colonies. Migration of chondrocytes to the periphery of the alginate bead was visible after 1 week of culture. Perfusion bioreactor with low shear stress and alginate hydrogel improve cell isolation and expansion and eliminate cell passaging and enhance colony forming unit of UC-MSCs.

Therapeutic abortion and ectopic pregnancy: alternative sources for fetal stem cell research and therapy in Iran as an Islamic country Abstract Regenerative medicine as a background of stem cell research and therapy has a long history. A wide variety of diseases including Parkinson's disease, heart diseases, multiple sclerosis, spinal cord injury, diabetes mellitus and etc. are candidate to be treated using different types of stem cells. There are several sources of stem cells such as bone marrow, umbilical cord, peripheral blood, germ cells and the embryo/fetus tissues. Fetal stem cells (FSCs) and embryonic stem cells (ESCs) have been described as the most potent stem cell source. Although their pluri- or multipotent properties leads to promising reports for their clinical applications, owning to some ethical and legal obstacles in different communities such as Muslim countries, care should be taken for therapeutic applications of FSCs and ESCs. Derivation of these cell types needs termination of pregnancy and embryo or fetus life that is prohibited according to almost all rules and teaches in Muslim communities. Abortion and termination of pregnancy under a normal condition for the procurement of stem cell materials is forbidden by nearly all the major world religions such as Islam. Legislated laws in the most of Muslim countries permit termination of pregnancy and abortion only when the life of the mother is severely threatened or when continuing pregnancy may lead to the birth of a mentally retarded, genetically or anatomically malformed child. Based on the rules and conditions in Islamic countries, finding an alternative and biologically normal source for embryonic or fetal stem cell isolation will be too difficult. On the one hand, Muslim scientists have the feasibility for finding of genetically and anatomically normal embryonic or fetal stem cell sources for research or therapy, but on the other hand they should adhere to the law and related regional and local rules in all parts of their investigation. The authors suggest that the utilization of ectopic pregnancy (EP) conceptus, extra-embryonic tissues, and therapeutic abortion materials as a valuable source of stem cells for research and medical purposes can overcome limitations associated with finding the appropriate stem cell source. Pregnancy termination because of the mentioned subjects is accepted by almost all Islamic laws because of maternal lifesaving. Also, there are no ethical or legal obstacles in the use of extra-embryonic or EP derived tissues which lead to candidate FSCs as a valuable source for stem cell researches and therapeutic applications.