bluuebunny/crossref_metadata_2025_split huggingface dataset:
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

Abstract
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.
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.
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.
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.
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.