bluuebunny/crossref_metadata_2025 huggingface dataset:
A phase 1 study of SGN-B6A, an antibody-drug conjugate targeting integrin beta-6, in patients with advanced solid tumors (SGNB6A-001, Trial in Progress).
Authors: Patnaik Amita , Calvo Emiliano , Piha-Paul Sarina Anne Anne , Hollebecque Antoine , Galvao Vladimir , Lopez Juanita Suzanne , Braiteh Fadi S. , Sanborn Rachel E. , Zhou Peigen , Nazarenko Natalya N. , Dowlati Afshin
Published: June 2021

TPS3144

Background: The extracellular matrix (ECM) plays an important role in solid tumor pathogenesis and is a major focus of research and therapeutic targeting. Integrin beta-6 is a cell surface receptor that interacts with the ECM to mediate cellular adhesion. Integrin beta-6 is overexpressed in numerous solid tumors and its expression is a negative prognostic marker in cancers including colorectal, non-small cell lung, gastric, and cervical cancers. SGN-B6A is an investigational vedotin, an antibody-drug conjugate directed against integrin beta-6 to selectively deliver the cytotoxic agent monomethyl auristatin E, which binds tubulin and induces apoptosis. In multiple xenograft models, treatment with SGN-B6A resulted in tumor growth delay and regression in tumor volume when compared to non-binding control. Methods: SGNB6A-001 (NCT04389632) is a phase 1, first-in-human, open-label, multicenter study designed to evaluate the safety, tolerability, pharmacokinetics (PK), and antitumor activity of SGN-B6A in adults with select advanced solid tumors. Primary objectives are to evaluate the safety and tolerability of SGN-B6A in patients with advanced solid tumors, identify the maximum tolerated dose, and identify a recommended dose and schedule. The study has 2 parts: dose escalation (Part A) and dose expansion with multiple disease-specific cohorts and a biology cohort (Part B). SGN-B6A will initially be given by intravenous infusion on Days 1, 8, and 15 of 21-day cycles. The dose escalation (Part A) will be conducted using the modified toxicity probability interval method to determine a dose that demonstrates a dose-limiting toxicity rate of 25% with a 5% margin. The dose and schedule for Part B will be determined based on evaluation of safety, PK, and pharmacodynamic biomarkers. Response evaluations will be based on RECIST v1.1. Patients must be ≥18 years old and have histologically or cytologically confirmed metastatic or unresectable solid malignancy within one of the following tumor types: non-small cell lung cancer, head and neck squamous cell cancer, breast cancer, esophageal cancer, ovarian cancer, cutaneous squamous cell cancer, exocrine pancreatic adenocarcinoma, bladder cancer, cervical cancer, or gastric cancer. After an appropriate dose and schedule are determined in Part A, safety and preliminary antitumor efficacy of SGN-B6A will be evaluated in indication-specific cohorts (Part B). This study is ongoing in sites across North America and Europe. Clinical trial information: NCT04389632.
A multicenter open-label phase 1 study evaluating the safety and tolerability of HMPL-306 in patients with locally advanced or metastatic solid tumors with IDH mutations.
Authors: Janku Filip , Kauh John S. , Tucci Christopher , Yang Zhao , Kania Marek K. , Alese Olatunji B.
Published: June 2021

TPS3159

Background: Isocitrate dehydrogenase (IDH) is a rate-limiting tricarboxylic acid cycle enzyme with 3 isoforms. Mutations in IDH1 and IDH2 result in gain-of-function activity that can cause tumor formation and/or progression and have been associated with various tumor types. Therefore, selective, single mutant IDH (mIDH) isotype inhibitors (mIDH1 or mIDH2) can lead to insufficient efficacy and the potential for tumor resistance. HMPL-306 is an innovative, small-molecule, orally available, highly selective, potent inhibitor of both mIDH1 and mIDH2. Clinical development of a compound that concurrently targets, inhibits, and suppresses multiple mIDHs could lead to significant and durable clinical benefit for patients (pts) with solid tumors harboring IDH mutations. Methods: This is a phase 1, open-label, dose escalation (Part 1) and dose expansion (Part 2) study to evaluate the safety, tolerability, pharmacokinetics (PK), pharmacodynamics (PD), and preliminary efficacy of HMPL-306 in pts ≥18 years with locally advanced or metastatic solid tumors with any IDH mutations. HMPL-306 will be administered orally, once daily in a 28-day continuous dosing treatment cycle. The HMPL-306 dose will be escalated in Part 1 according to the modified toxicity probability interval-2 (mTPI-2) design in 4 cohorts in approximately 15-20 pts: 50, 100, 150, and 200 mg. Eligible pts must have locally advanced or metastatic solid tumors with IDH1 or IDH2 mutations. The primary objectives are to evaluate safety, dose limiting toxicities (DLTs), tolerability, maximum tolerated dose (MTD), recommended phase 2 dose (RP2D), and PK. Approximately 95 pts will be enrolled at the RP2D in Part 2 to further characterize the safety, tolerability, PK, PD, and preliminary anti-tumor activities of HMPL-306. Part 2 will include 5 dose expansion cohorts: cholangiocarcinoma (n = 20), skeletal chondrosarcoma (n = 20), low-grade glioma (n = 20), perioperative low-grade glioma (n = 15), any other solid tumor harboring an IDH1/2 mutation (n = 20). All pts will continue treatment until disease progression, unacceptable toxicity, withdrawal of consent, or at the investigator’s discretion. Safety will be assessed based on reports of adverse events including clinical laboratory testing, vital signs, physical examinations, and electrocardiograms. All pts who receive any study treatment will be included in safety and efficacy analyses. Antitumor activity based on investigator-assessed overall response will be evaluated using descriptive analyses. Objective response rate will be calculated with 95% confidence interval using the Clopper-Pearson method. The Kaplan-Meier method will be used to summarize the time-to-event data such as progression-free survival and duration of response. No statistical hypothesis testing is planned. Enrollment started February 2021.
Neoadjuvant chemoradiotherapy with sequential ipilimumab and nivolumab in rectal cancer (CHINOREC): A prospective randomized, open-label, multicenter, phase II clinical trial.
Authors: Laengle Johannes , Kuehrer Irene , Pils Dietmar , Kabiljo Julijan , Stift Judith , Herbst Friedrich , Dauser Bernhard , Monschein Matthias , Razek Peter , Haegele Stefanie , Huller Wolfgang , Fuegger Reinhold , Geinitz Hans , Petzer Andreas L. , Bitterman Clemens , Laengle Friedrich , Tamandl Dietmar , Widder Joachim , Schmid Rainer , Bergmann Michael
Published: June 2021

TPS3623

Background: Immune checkpoint inhibitors (ICI), such as ipilimumab (anti-cytotoxic T-lymphocyte-associated protein 4) or nivolumab (anti-programmed cell death protein 1) have been proven to be an effective strategy in solid cancers. However, ICI seem not to be effective in microsatellite stable (MSS) cancers. As they might lack an immunogenic priming, radiotherapy (RT) is capable to induce an immunogenic cell death (ICD) and subsequently an immunogenic tumor immune microenvironment (TIME). Thus, RT might restore the susceptibility of MSS tumors to ICI and consequently leading to an effective anti-tumor immune response. Methods: This is a prospective, randomized, open-label, multicenter, phase II investigator-initiated clinical trial (IIT), including patients with locally advanced rectal cancer (LARC). Patients receive either neoadjuvant chemoradiotherapy (CRT) alone (50 Gy in 2 Gy fractions over 25 working days + capecitabine 1650 mg/m2/d PO) or in combination with ipilimumab (1 mg/kg IV on day 7) and nivolumab (3 mg/kg IV on day 14, 28 and 42). Patients will undergo surgery within 10-12 weeks post CRT. The primary endpoint is incidence of treatment-emergent adverse events (AEs) assessed by the Clavien-Dindo classification of surgical complications and the common terminology criteria of adverse events (CTCAE). Secondary objectives are radiographic and pathological therapy response. Serial liquid (plasma, serum and peripheral blood mononuclear cells) and tissue biopsies will be taken before, during and after neoadjuvant treatment. Genomic, transcriptomic, epigenomic and proteomic pattern of liquid and tissue biopsies, as well as the immune cell infiltrate of resected specimen, will be correlated with therapy response and clinical outcome. Currently 8 of planned 80 patients have been enrolled. Registration numbers: NCT no. NCT04124601, EudraCT no. 2019-003865-17. Clinical trial information: NCT04124601.
AdvanTIG-203: A randomized phase 2 study comparing anti-TIGIT ociperlimab plus tislelizumab versus tislelizumab plus placebo as second-line treatment in patients with advanced or recurrent esophageal squamous cell carcinoma (ESCC) expressing programmed death-ligand 1 (PD-L1).
Authors: Xu Rui-hua , Kim Sung-Bae , Tougeron David , Zuo Yunxia , Yang Haiyuan , Zhang Juan , Shi Jingwen , Van Cutsem Eric
Published: June 2021

TPS4150

Background: The programmed death-1 (PD-1)/PD-L1 pathway plays an important role in tumor induced immunosuppression. PD-L1 overexpression is observed in approximately 30–60% of esophageal cancers and is associated with poor prognosis. Anti-PD-1 agents demonstrate moderate efficacy in PD-L1-positive esophageal cancer in terms of response rate and overall survival, however, long-term outcomes remain poor due to primary and secondary resistance driven by tumor immune escape. The T-cell immunoglobulin and immunoreceptor tyrosine-based inhibition motif domain (TIGIT) is upregulated on T-cells and natural killer cells in multiple solid tumors, which can inhibit anticancer immune responses. Ociperlimab (BGB-A1217) is a novel, humanized, monoclonal antibody that binds TIGIT with high specificity and affinity, blocking the interaction with its ligands on tumor cells. Preclinical and clinical studies suggest that dual targeting with anti-TIGIT and anti-PD-1 antibodies produces synergistic immune cell activation and enhanced antitumor activity. Methods: AdvanTIG-203 is a phase 2, global, randomized, double-blind, placebo-controlled study (NCT04732494) of patients with unresectable, locally advanced, recurrent or metastatic ESCC, who progressed on or after 1st line systemic therapy and whose tumors express PD-L1 (visually estimated combined positive score ≥10%). After stratification by Eastern Cooperative Oncology Group performance status (0 or 1), number of metastatic sites (≤1 or ≥2) and region (Asian or non-Asian), 280 patients will be randomized (1:1) to either ociperlimab 900 mg intravenous (IV) plus tislelizumab 200 mg IV every 3 weeks (Q3W), or tislelizumab plus placebo Q3W, until disease progression (per RECIST v1.1), unacceptable toxicity, death or withdrawal of consent. Co-primary endpoints are investigator-assessed overall response rate (ORR) and overall survival (OS) in the intention-to-treat population. A sample size of 280 patients was estimated to provide approximately 94.8% power to detect a 20% difference in ORR at a one-sided significance level of 0.025. With 198 deaths, the study was estimated to provide approximately 86% power to detect a hazard ratio of 0.65 for OS. Secondary endpoints are ORR by independent review, progression-free survival, duration of response, disease control rate, and clinical benefit rate per investigator and independent assessment, cancer-specific health-related quality of life (HRQoL), and safety. Exploratory endpoints include but are not limited to expression of TIGIT, CD226, CD155, CD112, and PD-L1, pharmacokinetics, immunogenicity, and generic HRQoL measures. Clinical trial information: NCT04732494.
Camrelizumab plus apatinib combined with TACE and cryoablation in the first-line treatment of advanced hepatocellular carcinoma.
Authors: Xing Wenge , Guo Zhi
Published: June 2021

TPS4160

Background: Hepatocellular carcinoma (HCC) is a common cancer in the world, a leading cause of cancer-related death, and especially in China. Most of the HCC patients are diagnosed at an advanced stage and require a multidisciplinary approach. The IMbrave 50 trial has reported the successful efficacy of atezolizumab and bevacizumab combination therapy in advanced hepatocellular carcinoma, which indicate the potential efficacy of combination of immunotherapy and antiangiogenesis therapy in HCC patients. In some studies, the combinatorial approaches with immunotherapy and liver directed therapies such as transarterial chemoembolization (TACE), radiofrequency ablation (RFA), microwave ablation (MWA), and cryoablation are explored. Most combined interventional therapies reveal their enormous advantages as compared with any single therapeutic regimen alone, which may result from the immunologic enhancement effect of the multimodel therapy. In this study, we evaluated the efficacy and safety of combined therapy with camrelizumab plus apatinib mesylate and TACE plus cryoablation in patients with advanced HCC. Methods: This study was an open-label, single-arm, single centre, phase 2 trial in patients who were diagnosed with advanced HCC. Patients who meet the following criterias will be enrolled: (1) 18 - 75 years old; (2) Child-Pugh classification A or B(≤7);(3) Barcelona Clinic Liver Cancer stage B or C, or China liver cancer staging (CNLC) stage IIb̃IIIa; (4) Eastern Cooperative Oncology Group Performance Status (ECOG PS) score of 0–1; (5) no history of previous systematic treatment; (6) expected life expectancy of more than 12 weeks; (7) adequate organs function. The key exclusion criteria were history of active autoimmune disease, or concurrent medical use of immunosuppressive medications or immunosuppressive doses of systemic corticosteroids. Eligible patients received camrelizumab 200 mg intravenously every 2 weeks and apatinib 250 mg orally once per day continuously in a treatment cycle of 4 weeks, treatment continued until 1 year or development of unacceptable toxicity or progression of disease. TACE was administrated at the first treatment cycles on day 1or 2, the chemotherapy regimens included 100-150mg oxaliplatin, 750-1000mg fluorouracil, or 30-50 mg lobaplatin, raltitrexed 2-4mg, and epirubicin 40-80 mg. Two or three weeks after the TACE, percutaneous cryoablation was performed under CT guidance. TACE and cryoablation was given as combination therapy and the periods were assessed by the investigator. The primary endpoint is objective response rate (complete or partial response according to mRECIST) and Progression-Free-Survival (Time ranges from random to the first occurrence of disease progression or death from any cause). This trial is registered with Chinese Clinical Trials Registry, ChiCTR2100043044, and is ongoing. Clinical trial information: ChiCTR2100043044.
Biologically optimized schedule of gemcitabine and nab-paclitaxel regimen in metastatic pancreatic adenocarcinoma.
Authors: Abushahin Laith I. , Noonan Anne M. , Hays John L. , Malalur Pannaga G. , Manne Ashish , Jin Ning , Mittra Arjun , Elkhatib Rifat T. , Roychowdhury Sameek , Williams Terence Marques
Published: June 2021

TPS4168

Background: Metastatic pancreatic adenocarcinoma has a poor prognosis, and improvements in therapy have been challenging. Alongside efforts in developing novel agents, there is a need to optimize and maximize the benefit of currently approved drugs. Gemcitabine + nab-paclitaxel is a frequently used regimen for pancreatic adenocarcinoma. Nab-paclitaxel is albumin–bound chemotherapy; hence the role of albumin uptake is critical for its effect. Caveolae are small membrane invaginations essential for transendothelial albumin uptake. Cav-1 is the principal structural component of caveolae. Williams and colleagues have published a series of preclinical studies demonstrating that tumor cell-specific Cav-1 expression directly correlates with albumin and albumin-bound chemotherapy uptake and subsequent apoptotic response in tumor cells. In vitro studies showed that exposure of pancreatic cancer cells to Gemcitabine resulted in up-regulation of Cav-1 peaking 48 hours after gemcitabine exposure. This Cav-1 up-regulation correlated with increased temporal albumin cellular uptake. In addition, Williams and colleagues noted that exposure of pancreatic cancer cell lines to Gemcitabine resulted in a time–specific re-entry of cells into the G2/M phase (nab-paclitaxel cytotoxicity phase) between 48-60 hours after gemcitabine treatment. Collectively this data suggest that infusing nab-paclitaxel after 48 hours of gemcitabine infusion would be optimal for both increased uptake as well as increased susceptible tumor cells. We had previously shown this effect on multiple cell lines as well as mouse models. Methods: This is a phase II trial; patients will receive a standard of care chemotherapy regimen consisting of FDA-approved Gemcitabine + nab-paclitaxel with modification of the schedule to deliver nab-paclitaxel 48 hours (2 days) after gemcitabine infusions. The primary endpoint is ORR, with a null hypothesis of 20% vs. a target of 35%. Employing a 2-stage design (minimax) and assuming 80% power and a 0.05 significance level, a total of 53 patients will be required. In the first stage, if at least 7/31 patients respond to therapy, an additional 22 patients will be added for a total of 53 patients. The study will be terminated early if ≤ six patients respond in the first stage. Observation of response in at least 16/53 patients would be required to warrant further investigation of this infusion schedule of combination therapy. The secondary endpoints include the safety of the regimen schedule, Relative dose intensity, disease control rate, PFS, and OS. The trial opened to enrollment in June 2020 and is accepting patients. Clinical trial information: NCT04115163.
ENGOT-ov60/GOG3052/RAMP 201: A phase 2 study of VS-6766 (dual RAF/MEK inhibitor) alone and in combination with defactinib (FAK inhibitor) in recurrent low-grade serous ovarian cancer (LGSOC).
Authors: Banerjee Susana N. , Monk Bradley J. , Van Nieuwenhuysen Els , Moore Kathleen N. , Oaknin Ana , Fabbro Michel , Colombo Nicoletta , O'Malley David M. , Coleman Robert L. , Pachter Jonathan A. , Koustenis Andrew G. , Patrick Gloria , Leonard Lorna , Grisham Rachel N.
Published: June 2021

TPS5603

Background: VS-6766 is a unique small molecule inhibitor that blocks MEK kinase activity and RAF phosphorylation of MEK. This mechanism of blockade has been shown to limit compensatory MEK activation, thereby potentially enhancing efficacy of MEK inhibition. Defactinib, (VS-6063), an orally active small molecule, is a potent adenosine 5'- triphosphate (ATP) competitive, reversible inhibitor of focal adhesion kinase (FAK). Defactinib has shown synergistic activity with BRAF and MEK inhibitors in both in vitro and in vivo solid tumor models. Prior molecularly unselected studies with single agent MEK inhibitors have shown response rates up to 26% in recurrent LGSOC. A third of patients with recurrent LGSOC harbor somatic KRAS mutations. FAK inhibition has been shown to induce tumor regression when combined with RAF, MEK or RAF/MEK inhibitors in in vivo models of KRAS mutant ovarian cancer. The combination of VS-6766 and defactinib is currently being evaluated in the ongoing Investigator Sponsored FRAME study (NCT03875820). In this proof of concept study, durable objective responses have been reported in recurrent LGSOC patients, particularly those with KRAS mutations including patients who have had a prior MEK inhibitor (Banerji et al AACR 2020). Based on preclinical studies demonstrating efficacy of both VS-6766 and the VS-6766/defactinib combination and preliminary results of the FRAME study, the phase II ENGOT-ov60/GOG3052 has been developed in recurrent LGSOC. Methods: This is a Phase II, adaptive, two-part, multicenter, parallel cohort, randomized, open label study designed to evaluate the efficacy and safety of VS-6766 versus VS-6766 in combination with defactinib (NCT04625270). The study will be conducted in two parts. Part A will determine the optimal regimen based on confirmed overall response rate (independent radiology review) in KRAS-mutated LGSOC. Part B will determine the efficacy of the optimal regimen identified in Part A in KRAS-mutated and KRAS wild-type LGSOC. The minimum expected enrollment is 52 subjects with KRAS-mutated tumors (32 subjects in Part A and 20 in Part B) and 36 with KRAS wild-type tumors in Part B. Patients will be randomized to receive VS-6766 (4.0 mg PO, twice weekly 3 weeks on, 1 week off) or VS6766 with defactinib (VS-6766 3.2 mg PO, twice weekly + defactinib 200 mg PO BID 3 weeks on, 1 week off) till progression. Key inclusion criteria include histologically confirmed LGSOC, presence of KRAS mutation (Part A), prior systemic therapy for metastatic disease and up to 1 prior line of MEK/RAF inhibitor therapy permitted. This international study is open to enrollment. Clinical trial information: NCT04625270.
Improving patient and caregiver understanding of risks and benefits of immunotherapy for melanoma or lung cancer.
Authors: Petrillo Laura A , Zhou Ashley , Volandes Angelo E. , Sullivan Ryan J. , El-Jawahri Areej , Greer Joseph A. , Temel Jennifer S.
Published: June 2021

TPS6596

Background: Immune checkpoint inhibitors (ICI) extend survival for patients with advanced cancer, particularly melanoma and lung cancer, though responses are heterogeneous and treatment may be complicated by immune-related adverse events that are important for patients and their caregivers to recognize. The aim of this trial is to evaluate the feasibility and preliminary efficacy of an educational video and question prompt list (QPL) in improving patients’ and caregivers’ understanding of what to expect from immunotherapy. Methods: In this randomized controlled trial of a novel educational intervention to improve immunotherapy knowledge, we will enroll 140 adult patients with advanced melanoma or lung cancer (small cell or non-small cell) who have a plan to initiate therapy with an ICI and their caregivers. Patients assigned to the intervention will receive a link to a video about the risks and benefits of ICI treatment developed by the study team as well as an ICI-focused QPL that includes questions about the goal and likelihood of benefit of ICIs. We will enroll the first ten patients in an open pilot and we will refine the intervention and study procedures based on pilot findings. We will randomize the remaining 130 patients to receive either the intervention or a usual care control. Randomization will be carried out using the permuted block approach with stratification by cancer type, and patient-caregiver dyads will be assigned to the same study arm. Participants on both arms will complete surveys at enrollment (baseline), 72 hours post-enrollment, and 6 weeks post-enrollment. The primary outcome of the study is feasibility of intervention delivery, defined as 70% of approached patients enrolling in the trial and 80% of enrolled patients watching the video, reviewing the QPL and completing the first assessment. We will also evaluate the preliminary efficacy of the intervention in 1) improving patient and caregiver knowledge, measured by a survey of knowledge questions that we developed and previously pilot tested with a sample of 105 patients; 2) enhancing patient-clinician communication, assessed by evaluating the number of questions patients asked in audio-recorded visits with their oncology clinicians after reviewing the QPL; and 3) reducing anxiety, measured by the State and Trait Anxiety Index. We will assess change in knowledge scores and anxiety from baseline to 72 hours post-enrollment and 6-weeks post-enrollment using the analysis of covariance model, adjusting for baseline scores and relevant covariates. The number of questions asked by patients and caregivers will be assessed by coding transcripts of oncology visits and comparing between arms using the negative binomial model. Study accrual to the open pilot phase began in February 2021. Current enrollment: n = 5. Clinical trial information: 04670445.
Winship 4851-19: A pilot study of neoadjuvant and adjuvant cemiplimab for high-risk cutaneous squamous cell carcinoma.
Authors: Lowe Michael C. , Yushak Melinda Lynne , Delman Keith A. , Rizzo Monica , Claar Caroline , Schmidt Allyson , Switchenko Jeffrey M. , Lawson David H. , Kudchadkar Ragini Reiney
Published: June 2021

TPS9593

Background: The PD-1 inhibitor cemiplimab was approved in 2018 for treatment of locally advanced or metastatic cutaneous squamous cell carcinoma (cSCC) that is not curable with surgery or radiation. This approval was based on the results of the phase 2 EMPOWER-CSCC-1 trial, which demonstrated an objective response rate of 47% with a significant number of these patients experiencing a durable response. However, patients with high risk cSCC that are able to undergo curative intent surgery are not candidates for checkpoint inhibitor therapy but still experience high rates of recurrence and/or systemic progression even when offered adjuvant radiotherapy. In light of data using checkpoint inhibitor therapy in the neoadjuvant setting in other cutaneous malignancies, we hypothesized that cemiplimab therapy would improve surgical outcomes and reduce long-term recurrence rates in patients with high-risk resectable cSCC if used in the perioperative setting. Methods: Winship 4851-19 is a single arm pilot study of cemiplimab in the neoadjuvant and adjuvant setting for high-risk resectable cSCC (NCT04428671). In the neoadjuvant phase, patients receive three doses of cemiplimab every three weeks followed by standard of care surgery. Radiation may be offered when clinically appropriate at the discretion of the investigator. In the adjuvant phase (following surgery +/- radiation), patients receive cemiplimab every three weeks to complete one year total of treatment. Eligible patients must have surgically resectable histologically proven high risk cSCC defined as: nodal disease with extracapsular extension or one node ≥20mm; in transit metastases > 2cm from primary lesion; T4 head and neck primary tumor; perineural invasion; or recurrent cSCC with concurrent ≥N2b nodal disease, size ≥4cm or bony invasion, or poorly differentiated histology. Patients cannot have received prior immunotherapy and must have a ECOG performance status of 0 or 1. Primary objective is to establish pathologic response rate. Secondary objectives include assessments of local and distant recurrence and overall survival rates. We also plan to evaluate the immune profile of fresh tumor and blood to assess the impact of neoadjuvant cemiplimab on the tumor microenvironment and circulating immune responses. To date 5 of 20 patients have been enrolled; this sample size was selected based on feasibility and ability enroll within a timely fashion. Clinical trial information: NCT04428671.
The Rhetorical Transformations and Policy Failures of Prescription Drug Pricing Reform under the Trump Administration
Authors: Sachs Rachel E.
Published: June 2021

Throughout his four years in office, President Trump made prescription drug pricing a focus of his policy agenda. President Trump not only used strong language to criticize the pharmaceutical industry and its practices but also introduced ambitious reform policies that had previously lacked acceptance among Republican policy makers. President Trump appears to have been successful in developing a new populist form of rhetoric that Republicans can use in support of novel drug pricing reforms such as the ones his administration considered. From a policy perspective, however, the Trump administration failed to implement any of their more ambitious reform ideas. This article considers three of the Trump administration's signature policies—state-sponsored prescription drug importation, Medicare Part B international reference pricing, and reforms to the Medicare Part D rebate system—and explores how they represent both the political ambitions and policy failures of the Trump administration. The fate of the Trump administration's prescription drug proposals also reveals lessons about innovation and access, which will be important to ongoing drug pricing reform efforts.
Transition in successors’ behavior and mindset while managing long-lived small and medium-sized manufacturing enterprises: a qualitative study
Authors: Suzuki Hiroo , Kino Yasunobu
Published: June 2021

Background: There have been many studies conducted on succession, which can be considered as the most important issue in family businesses. However, most of these previous studies have focused only on the early stage of succession, uncovering the role of the predecessor and the successor. Only a few studies have made efforts to examine the total lifecycle of succession. The purpose of this study is to explore the process of the transition in successors' behavior and mindset while managing long-lived small and medium-sized manufacturing enterprises throughout the lifecycle of succession.

Methods: Semi-structured interviews were conducted with six successors of small and medium-sized manufacturing companies who are more than half a century old. Their answers were analyzed using the Modified-GTA method to construct a hypothetical model.

Results: In total, 46 concepts, four categories, 17 subcategories, and one core category were generated. An analysis result diagram using all concepts and categories was formed. From the observation of this diagram, the successors gained confidence in management through the dilemma between autonomy and constraint in the early stage of succession, which was found in previous research. Following the initial stage, the successors responded to the crisis caused by market constraints and created autonomous strategies in their businesses.

Conclusions: By experiencing repetitive crises, the successors tend to acquire new perspectives toward the naturally occurring crises. This change of premise by the successors is considered as the process of double-loop learning. Relationships inside and outside the company influence the generation of this viewpoint. From a long-term perspective, a sense of unity with employees, stable employment, and the pursuit of enjoyment constitute the successors' own values in this model.
ANXIETY-DEPRESSIVE DISORDERS IN PATIENTS WITH ARTERIAL HYPERTENSION
Authors: MOSKALENKO OLGA , YASKEVICH ROMAN
Published: June 2021

Our article presents a review of the literature and considers the most pressing problem of modern medicine - a combination of anxiety-depressive states in patients with cardiovascular diseases, which are more common in people of working age, having a negative impact on the quality of life of patients, contributing to the deterioration of physical, mental and social adaptation, which further leads to negative socio-economic consequences.
Management of temporary epicardial pacing wires in the cardiac surgical patient
Authors: Francis Jeevan , Prothasis Sneha , Hegde Rutwik , Attia Antony , Buchan Keith
Published: June 2021

Temporary epicardial pacing wires are used after cardiothoracic surgery to maintain a stable cardiac rhythm. They must be distinguished from the more commonly encountered transvenous temporary pacing wires, which are often used in coronary care units for the same purpose. Patients with temporary epicardial pacing wires may be transferred to hospital wards where these wires are not usually encountered, such as COVID wards, the general intensive care unit, the coronary care unit or general surgical wards if a laparotomy was required in the early period following cardiac surgery. Serious complications may arise in managing patients with temporary epicardial pacing wires, which are well known in the cardiothoracic unit but not so well known elsewhere in the hospital. This article discusses the dangers associated with the management of temporary epicardial pacing wires in adult patients, some of which are common to temporary transvenous pacing wires and others are unique to temporary epicardial pacing wires.
Recurrent venous leg ulcers: management in general practice
Authors: Brown Annemarie
Published: June 2021

Venous leg ulcers commonly recur. Annemarie Brown highlights some self-care strategies that patients can use to reduce their risk

Chronic venous leg ulcers are commonly seen in general practice and although healing rates for leg ulcers have improved, recurrence rates are high with around 60–70% reported to recur after healing. The primary prevention strategy is the life-long wearing of compression hosiery; however, compliance is low for several reasons including lack of understanding of the need to wear compression hosiery and difficulties applying and removing it. Self-care strategies such as physical exercise and mobility, leg elevation and appropriate skin care, can help to prevent recurrence of venous leg ulcers. Practice nurses are ideally placed to provide this advice, which can help improve patient's quality of life while reducing the financial burden of treating open ulceration for the NHS.
An Adaptive Robust Controller for Hydraulic Robotic Manipulators with a Flow-Mapping Compensator
Authors: Zhang Fu , Zhang Junhui , Xu Bing , Zong Huaizhi
Published: June 2021

Proportional directional control valves have flexible control functions for the control of various hydraulic manipulators. It is foreseeable that the application of proportional directional control valves will be further expanded. However, due to its own structure, its important parameter, flow gain, is complex, and it has a complex functional relationship with valve opening and temperature. The variable flow gain reduces the performance of a strictly derived nonlinear controller. Therefore, it is necessary to consider the nonlinearity of flow gain in the controller design. In order to solve the above problems, this paper proposes an adaptive robust controller for a hydraulic manipulator with a flow-mapping compensator, which takes into account the nonlinear flow gain and improves the performance of the nonlinear controller. First, we established an adaptive robust controller of the hydraulic manipulator to obtain the load flow of the control input valve. Then, the function of flow gain, input voltage, and temperature are calibrated offline using cubic polynomial, and the flow-mapping compensator is obtained. Finally, we calculate the input voltage based on the flow-mapping compensator and load flow. The flow-mapping compensator further reduces the uncertainty of the model and improves the robustness of the system. By using the proposed controller, the control accuracy of the hydraulic manipulator is significantly improved.
Targeted Attack through Network Fingerprinting
Authors: Marechal Emeline , Donnet Benoit
Published: June 2021

Nowadays, simple tools such as traceroute can be used by attackers to acquire topology knowledge remotely. Worse still, attackers can use a lightweight fingerprinting technique, based on traceroute and ping, to retrieve the routers brand, and use that knowledge to launch targeted attacks.

In this paper, we show that the hardware ecosystem of network operators can greatly vary from one to another, with all potential security implications it brings. Indeed, depending on the autonomous system (AS), not all brands play the same role in terms of network connectivity and network usage (MPLS vs. standard traffic). An attacker could find an interest in targeting a specific hardware vendor in a particular AS, if known defects are present in this hardware, and if the AS relies heavily on it for forwarding its traffic.
TPA Auditing to Enhance the Privacy and Security in Cloud Systems
Authors: Kumar Sunil , Kumar Dilip , Lamkuche Hemraj Shobharam
Published: June 2021

Over the last decade, many enterprises around the world migrating from traditional infrastructure to cloud resources in order to cut down operational and capital expenditure. With cloud computing, huge amount of data transactions is communicated between cloud consumers and cloud service providers. However, this cloud computing enables surplus security challenges associated to unauthorized access and data breaches. We proposed in this paper a trusted third-party auditor (TPA) model which uses lightweight cryptographic system and lightweight hashing technique to ensure data security and data integrity to audit the cloud users outsourced data from cloud service providers. With our proposed system, we solve the concern of data reliability using data correctness and verification analysis and error recovery analysis. The time complexity of our proposed system is less as compared with other TPA model. Our proposed system also shows resistance against various known cryptanalytic attacks, the performance and extensive compression technique of our proposed system are probably secure and highly proficient.
DDOS Detection on Internet of Things Using Unsupervised Algorithms
Authors: Odumuyiwa Victor , Alabi Rukayat
Published: June 2021

The increase in the deployment of IOT networks has improved productivity of humans and organisations. However, IOT networks are increasingly becoming platforms for launching DDOS attacks due to inherent weaker security and resource-constrained nature of IOT devices. This paper focusses on detecting DDOS attack in IOT networks by classifying incoming network packets on the transport layer as either “Suspicious” or “Benign” using unsupervised machine learning algorithms. In this work, two deep learning algorithms and two clustering algorithms were independently trained for mitigating DDOS attacks. Emphasis was laid on exploitation based DDOS attacks which include Transmission Control Protocol SYN-Flood attacks and UDP-Lag attacks. Mirai, BASHLITE and CICDDOS2019 datasets were used in training the algorithms during the experimentation phase. The accuracy score and normalized-mutual-information score are used to quantify the classification performance of the four algorithms. Our results show that the autoencoder performed overall best with the highest accuracy across all the datasets.
Development of NTFPs Sector for Income Generation and Environmental Conservation
Authors: Sundriyal Manju
Published: June 2021

Non-Timber Forest Products (NTFPs) are amongst the key global commodi-ties and an important component of international trade. They are importantin livelihoods of rural people all over the Himalayan region for meetingfood, medicine, construction materials, and income needs of subsistencecommunities. The sector needs focused developmental planning that canbring substantial economic and environmental benefit in the Uttarakhandstate. Based on an extensive analysis of three important categories of NTFPs,viz. medicinal plants, edible wild plants, and bamboo this paper highlightspotential of this sector for food security, income generation and environ-mental conservation by adopting a pro-people approach in Uttarakhand state.Suggestions have been provided for improving the existing framework andprogrammes that can maximize economic, social, cultural and ecologicalbenefits.
Politics of fear in Brazil: Far-right conspiracy theories on COVID-19
Authors: Kalil Isabela , Silveira Sofia Cherto , Pinheiro Weslei , Kalil Álex , Pereira João Vicente , Azarias Wiverson , Amparo Ana Beatriz
Published: June 2021

In this article, we present an analysis of narratives mobilised by extreme right-wing leader Jair Bolsonaro and his supporters in response to the COVID-19 pandemic in Brazil, from March to December 2020. Our research indicates that, throughout that year, despite changes in the categories used, fear was continuously mobilised by the Brazilian president connecting an alleged ‘communist conspiracy’ to the coronavirus pandemic by creating narratives around the terms ‘Chinese virus’ and ‘Chinese vaccine’. Mapping these conspiratorial discourses, we hope to better understand (1) how Bolsonaro converts conspiracy theories into official state discourse as well as public policy, and (2) how Bolsonaro and his mediatic representatives weaponise tensions between individual freedom and public healthcare and the scientific community. Taking this scenario into account, we analyse how Bolsonaro uses social fear during the pandemic as part of his permanent campaign in a process resulting in serious risks to both public health and democracy.
Material platform for realization of a “fiber-like” lossy mode resonance response in a simple Kretschmann–Raether geometry
Authors: Goswami Sumit , Sharma Ashwini Kumar
Published: June 2021

The lossy mode resonance (LMR) phenomenon is almost exclusively limited to fiber optics, since the thin film configuration yields a relatively shallow resonance dip compared to its fiber counterpart. In this Letter, we bridge this frustrating intensity gap between these basic configurations by choosing vacuum-deposited metallic indium-rich indium tin oxide as the coating material. LMR attenuation as high as

−

14.3

d
B

for transverse electric and

−

6.4

d
B

for transverse magnetic polarization is achieved experimentally via a commonly used Kretschmann–Raether geometry and that too for a film thickness of

≈

70

n
m

. Such a high degree of LMR response is attributed to the metallic indium generated interbands, leading to a high extinction coefficient in the visible range. A modified transfer matrix method, which takes into account the surface roughness of the films through application of the anisotropic Bruggeman effective medium approximation, is developed to realize the experimental LMR spectra numerically.
THE ROLE OF PROJECT MANAGEMENT IN THE INTEGRATION OF SCIENCE, EDUCATION AND BUSINESS
Authors: Akhmetova Z. B. , Kozhakhmetova A. K. , Asanova A. D.
Published: June 2021

Integration of science, education and business is a driver of economic competitiveness in the context of globalization and building an effective national innovation ecosystem. Project management is considered one of the main tools for improving the efficiency of commercialization projects that are the result of successful integration. The study aims to assess the relationship between project management and performance indicators of integration of science, education and business in the face of commercialization projects. The results of the study revealed that intensive use of the above processes increases the efficiency of projects. Moreover, critical processes were identified that positively affect the timing and cost of commercialization projects. Integration of science, education and business is an effective tool for sustainable development and competitiveness of States in the context of globalization and the formation of a knowledge-based economy and the construction of an effective national innovation ecosystem.
STUDY OF TARIFFS FOR TRANSPORT SERVICES IN THE EUROPEAN UNION COUNTRIES AND THE RUSSIAN FEDERATION
Authors: Kapelyuk Z. A. , Popova Y. V.
Published: June 2021

The article analyzes the experience of tariff regulation of the cost of passenger railway transportation services in the European Union and the Russian Federation. The features of tariff regulation are disclosed and eleven countries are classified according to the main categories.

Tariff policy for transport services is used to ensure the consistency of economic interests of consumers and is a problematic segment for all types of transport. The article deals with tariff regulation of the cost of services provided by the railway infrastructure. Comparison of domestic and foreign experience in pricing of transport services for further development of Russian Railways is carried out. The setting of tariffs and available discounts, as well as benefits for the purchase of tickets for trains in the countries of the European Union and Russia are considered. The indexation of tariffs for transportation services of Russian Railways depending on the period of the trip and the comfort of the car is analyzed.

Conclusions on the impact of mobile tariffs on economic efficiency, as well as the need to improve the tariff policy in the Russian Federation by involving foreign transport companies in implementation.
TOURISM INFRASTRUCTURE IMPROVING AS A PREREQUISITE FOR INCREASING THE CONTRIBUTION OF TOURISM TO THE REGIONAL ECONOMY
Authors: Mishchenko I. V. , Purichi V. V. , Gabrielyan E. E. , Lukhmanova G. K.
Published: June 2021

The tourism sector is becoming an increasingly significant component of the economy of many regions of Russia. However, the lack of the necessary infrastructure does not fully utilize its potential. The pandemic has become an incentive for the development of domestic tourism and at the same time exposed many problems. So, on the materials of the Altai Territory, the authors gave an assessment of the state of the tourist infrastructure of the region, as the basis of the tourist sphere. The most important recreational zones of the Altai Territory were considered. It was revealed that most of the tourist zones of the region face many infrastructure problems — the lack of accommodation, lighting, social infrastructure, poor-quality roads. At the same time, solving these problems is a prerequisite for the sustainable development of the region’s industry. To develop a strategy for the further development of the tourism sector, the authors carried a SWAT analysis of the tourism sector of the region, proposed ways to solve the identified problems. The developed proposals will improve the state of the industry as a whole (primarily the infrastructure component), as well as increase its contribution to the regional economy.
THE STUDY OF THE TERRITORIAL AND SECTORAL STRUCTURE OF THE RUSSIAN ECONOMY IN THE CONTEXT OF INTERREGIONAL INTEGRATION: TO THE FORMULATION OF THE PROBLEM
Authors: Trotskovsky A. Ya. , Sergienko A. M. , Rodionova L. V. , Perekarenkova Yu. A. , Sundeeva M. A.
Published: June 2021

The authors, taking into account the existing developments, reveal the scientific relevance of the topic, which consists in verifying the existing concepts of regional growth driving forces in relation to regions with an industrial or industrial-agrarian economy.

The authors describe the practical relevance of the study, which, according to the authors, consists in identifying the reasons inherent in the agro-industrial regions as a whole for their lag in socio-economic development.

For the first time, the question of studying the territorial and industrial structure and, in particular, one of its key elements-agro — industrial regions in the context of the formation and development of integration and cooperation processes is raised.

The article considers the most important aspect of the problem — the impact of integration on the development of agro-industrial regions, the possibility of the latter to enter the integration union on an equal partnership basis. The authors explain their position on this issue in a reasoned manner.

The article proposes a classification of agro-industrial regions of Russia by the size of the integration potential. The classification is based on two criteria: the level of socio-economic development and the degree of the region periphery.

At the end of the article, the main priority directions and tasks of the long-term development of the topic under consideration are listed.