bluuebunny/crossref_metadata_2025 huggingface dataset:
Phase II study of cabozantinib (cabo) combined with pembrolizumab (pembro) in metastatic or recurrent gastric and gastroesophageal adenocarcinoma (GEC) to overcome resistance to checkpoint inhibitors.
Authors: Dayyani Farshid , Thomas Chloe , Ung Gwendolyn , Taylor Thomas H
Published: January 2021

TPS253

Background: GEC is the third leading cause of cancer mortality and the fifth most common malignancy worldwide. Fluoropyrimidine and platinum-based combinations are the most commonly used 1L treatment regimens. There are few standard treatment options after 1st line regimens. In the 3L+ GEC Keynote-059 trial, objective response rate (ORR) with Pembro was 15.5% in PD-L1(+) vs. 6.4% in PD-L1(-) tumors. While the responses were durable, the 6-months PFS (6-PFS) was only 14.1% and the median PFS was 2.0 mo. This highlights the remaining unmet need for the majority of patients who either are refractory or develop disease progression following treatment with PD-1 inhibitors in GEC. Cabo plus checkpoint inhibitors have shown clinical benefit in various cancers including hepatocellular, renal cell (RCC), urothelial and castration-resistant prostate cancers. In the CheckMate-9ER trial, Cabo+Nivolumab improved both OS and PFS vs sunitinib in 1L RCC. In patients with RCC who had progression on anti-PD1 inhibitor treatment, Cabo showed promising activity with an ORR of 33% and DCR of 79% (ESMO 2018, abstract 3793). Hypothesis: Based on preclinical and clinical observations, Cabo might contribute to overcoming primary or secondary resistance to PD-1 blockade in GEC. Methods: Prospective, open label, non-randomized phase 2 trial. Eligibility: Diagnosis of GEC, 2+ line of treatment including previous fluoropyrimidine/platinum, ECOG 0-2, adequate organ function, prior checkpoint inhibitor if tumor PD-L1 CPS≥10%. Treatment: Cabozantinib 40mg PO daily, Pembrolizumab 200 mg IV on day 1 of 21d cycle. Primary objective: Feasibility of the combination and estimate of efficacy. Primary endpoint:PFS-6. Secondary objectives: OS, ORR, adverse events. Total number of patients to be enrolled N = 27. Current enrollment (Sep 2020) N = 10. Statistics: If the PFS-6 is > 25%, the study would be regarded as positive, in which case it is planned to expand patient enrollment into a larger single arm phase 2 trial with additional sites to establish the efficacy of the regimen. Clinical trial information: NCT04164979.
A phase III, double-blind, randomized study of nivolumab (NIVO) and ipilimumab (IPI), nivo monotherapy or placebo plus transarterial chemoembolization (TACE) in patients with intermediate-stage hepatocellular carcinoma (HCC).
Authors: Sangro Bruno , Harding James J. , Johnson Matthew , Palmer Daniel H. , Edeline Julien , Abou-Alfa Ghassan K. , Cheng Ann-Lii , Decaens Thomas , El-Khoueiry Anthony B. , Finn Richard S. , Galle Peter R. , Park Joong-Won , Yau Thomas , Begic Damir , Shen Yun , Neely Jaclyn , Sama Ashwin Reddy , Kudo Masatoshi
Published: January 2021

TPS349

Background: TACE is the most widely used locoregional therapy recommended for patients with intermediate-stage HCC (Barcelona Clinic Liver Cancer stage B). Despite the significant tumor responses that can be achieved with TACE, tumors commonly recur, progress, or are refractory. Clinical trials have explored the combination of TACE with tyrosine kinase inhibitors; however, these have not reported improved outcomes. HCC possesses a unique immunosuppressive microenvironment, which makes it an attractive target for immunotherapies, particularly immune checkpoint inhibitors. Furthermore, there is evidence that locoregional interventions induce changes in the immune environment that could promote synergy with checkpoint inhibitors. Preliminary data for the combination of TACE with nivolumab indicate an acceptable safety profile and promising efficacy (Harding et al. ASCO-GI 2020). NIVO monotherapy and NIVO+IPI combination therapy are both approved in the United States for patients with HCC previously treated with sorafenib. Together, these findings support investigation of TACE plus NIVO, IPI, or NIVO+IPI to address the therapeutic needs of patients with intermediate HCC. Methods: CheckMate 74W is a global, double-blind, placebo-controlled, 3-arm, randomized phase III trial. Patients with tumors that exceed the Beyond Milan and Up-to-7 criteria (7 being the sum of size [in centimeters] and number of tumors), eligible for TACE, with Eastern Cooperative Oncology Group performance status of 0 to 1 are eligible for enrollment. Patients must not have received prior locoregional therapies. Approximately 765 patients will be randomized in a 1:1:1 ratio to NIVO+IPI+TACE (arm A), NIVO+IPI placebo+TACE (arm B), or NIVO placebo+IPI placebo+TACE (arm C). Primary endpoints are the time to TACE progression (TTTP), assessed by blinded independent central review, and overall survival in arm A versus arm C. Secondary endpoints are TTTP and overall survival in arm B versus arm C, event-free survival, and progression-free survival. Clinical trial registry: NCT04340193. Clinical trial information: NCT04340193.
Phase III study of NUC-1031 + cisplatin vs gemcitabine + cisplatin for first-line treatment of patients with advanced biliary tract cancer (NuTide:121).
Authors: Knox Jennifer J. , McNamara Mairead Geraldine , Goyal Lipika , Cosgrove David , Springfeld Christoph , Sjoquist Katrin Marie , Park Joon Oh , Verdaguer Helena , Braconi Chiara , Ross Paul J. , De Gramont Aimery , Shroff Rachna T. , Zalcberg John Raymond , Palmer Daniel H. , Valle Juan W.
Published: January 2021

TPS351

Background: Biliary tract cancer (BTC) carries a poor prognosis and no first-line treatments are approved. The accepted global standard of care is gemcitabine + cisplatin (GemCis). NUC-1031 is a phosphoramidate transformation of gemcitabine designed to overcome key cancer resistance mechanisms that are associated with gemcitabine. Promising efficacy has been observed with single-agent NUC-1031 in a phase I study in advanced solid tumors and in the phase Ib ABC-08 study of NUC-1031 + cisplatin for first-line treatment of advanced BTC. Of 14 patients enrolled in 2 cohorts (NUC-1031 625 mg/m2 or 725 mg/m2 + cisplatin 25 mg/m2 on Days 1 and 8 of 21-day cycle), 1 had a CR and 6 had PRs, resulting in an unconfirmed ORR of 50%. This represents an approximate doubling of ORR over SoC. The combination was well-tolerated with no unexpected AEs or DLTs. The RP2D of NUC-1031 with cisplatin was 725 mg/m2. The tolerability profile, together with encouraging efficacy, suggested NUC-1031 + cisplatin may represent a more effective therapy than GemCis for BTC and led to initiation of a global registrational study. Methods: NuTide:121 is a Phase III, open-label, randomized study of NUC-1031 + cisplatin vs GemCis for first-line treatment of advanced BTC. Patients ≥18 years with histologically- or cytologically-confirmed BTC (including cholangiocarcinoma, gallbladder, or ampullary cancer), who have had no prior systemic chemotherapy for locally advanced/metastatic disease, are eligible. A total of 828 patients are being randomized (1:1) to either 725 mg/m2 NUC-1031 or 1000 mg/m2 gemcitabine, both with 25 mg/m2 cisplatin, administered on days 1 and 8 of 21-day cycles. Primary objectives are OS and ORR. Secondary objectives include PFS, safety, PK and patient-reported quality of life. In addition to the final analysis, three interim analyses, including two designed to support accelerated approval, are planned. The study has passed an initial safety analysis, with no protocol changes required. NuTide:121 is being conducted at approximately 130 sites across North America, Europe and Asia Pacific countries. Clinical trial information: NCT04163900.
Phase II trial of the PARP inhibitor, niraparib, in BRCA1-Associated Protein 1 (BAP1) and other DNA damage response (DDR) pathway deficient neoplasms including cholangiocarcinoma.
Authors: George Thomas J. , DeRemer David L. , Lee Ji-Hyun , Staal Stephen , Markham Merry Jennifer , Jones Dennie V. , Hosein Peter Joel , Daily Karen Colleen , Chatzkel Jonathan Alexander , Ramnaraign Brian Hemendra , Close Julia Lee , Murphy Martina Cathryn , Allegra Carmen Joseph , Rogers Sherise C. , ali azka , Hromas Robert A.
Published: January 2021

TPS354

Background: BRCA1-Associated Protein 1 (BAP1) is a critical regulator of the cell cycle, cellular differentiation, cell death, and DNA damage response. It also acts as a tumor suppressor. Preclinical models demonstrate significant synthetic lethality in BAP1 mutant cell lines and patient xenografts when treated with PARP inhibitors, independent of underlying BRCA status, suggesting this mutation confers a BRCA-like phenotype. BAP1 is mutated, leading to a loss of functional protein, in up to 30% of cholangiocarcinomas as well as several other solid tumors. Methods: This phase 2, open-label, single arm multicenter study aims to exploit the concept of synthetic lethality with the use of the PARP inhibitor niraparib in pts with metastatic relapsed or refractory solid tumors. Eligible pts with measurable metastatic and incurable solid tumors are assigned to one of two cohorts: Cohort A (histology-specific): tumors harboring suspected BAP1 mutations including cholangiocarcinoma, uveal melanoma, mesothelioma or clear cell renal cell carcinoma with tissue available for BAP1 mutational assessment via NGS or Cohort B (histology-agnostic): tumors with known DNA damage response (DDR) mutations (Table) confirmed by CLIA-approved NGS. Other key eligibility criteria include age ≥18 years, adequate cardiac, renal, hepatic function and Eastern Cooperative Oncology Group performance status of 0 to 1. Pts with known BRCA1 or BRCA2 mutations or prior PARPi exposure are excluded. Pts receive niraparib 200-300mg daily (depending on weight and/or platelet count) continuously. Primary endpoint is objective response rate with secondary endpoints of PFS, OS, toxicity and exploratory biomarker determinations. Radiographic response by RECIST criteria is measured every 8 weeks while on treatment. Cohort A has fully enrolled. Cohort B enrollment continues to a maximum of 47 total evaluable subjects with expansion cohorts allowable for histologic or molecular subtypes meeting pre-specified responses. NCT03207347 Clinical trial information: NCT03207347. [Table: see text]
A phase I/II trial to evaluate cabozantinib in patients with advanced hepatocellular carcinoma with Child-Pugh class B cirrhosis after first-line therapy.
Authors: Enzler Thomas , Parikh Neehar , Liao Chih-Yi , Kalyan Aparna , Hsieh David , Griffith Kent A. , Sahai Vaibhav
Published: January 2021

TPS357

Background: Hepatocellular carcinoma (HCC) is the 4th leading cause of cancer related death worldwide. HCC typically develops in patients with cirrhosis and has a 5-year survival estimate of 20%. Only patients with early stage disease may be eligible for a curative approach using local treatment and/or transplant. The majority of patient present with advanced HCC and will require systemic treatment for disease control. Several systemic therapies are FDA-approved for the treatment of HCC; however, they are only approved for patients with Child-Pugh class A cirrhosis. There are limited data and no approved second-line therapy for HCC with more advanced cirrhosis, including Child-Pugh class B, which represents a significant proportion of patients. The aim of this trial is to determine the safety and efficacy of cabozantinib, a multi-kinase inhibitor, in patients with HCC with Child-Pugh class B cirrhosis. Methods: This investigator-initiated, phase I/II study is enrolling 32 patients with advanced HCC, Child-Pugh B7 or B8, who have previously received first-line systemic treatment. Patients receive cabozantinib at one of 3 dose levels (20 mg, 40 mg, and 60 mg) with a starting dose level of 40 mg to evaluate the safety profile and obtain the recommended phase 2 dose (RP2D). The primary endpoint is assessment of dose-limiting toxicity with a null hypothesis greater than 35%. Secondary endpoints include ORR per RECIST v1.1, PFS, OS, and PK profile. Exploratory endpoints include whole exome/RNAseq analysis (including MET, VEGF, AXL, and immune signature), spatial profiling of immune markers by multiplex immunofluorescence, and specimen banking (tissue, blood and imaging). The trial design is based on the Time-To-Event modification of the Continual Reassessment Method (TiTE-CRM), which allows for continued monitoring of toxicity as a function of a dose-over-time, and is flexible with regard to the number of patients treated at a certain dose. The trial is open at University of Michigan as lead and coordinating site, and due to open at 3 additional high-volume centers. Clinical trial information: 04497038.
A phase II, open-label pilot study evaluating the safety and activity of liposomal irinotecan (Nal-IRI) in combination with 5-FU and oxaliplatin (NALIRIFOX) in preoperative treatment of pancreatic adenocarcinoma (NEO-Nal-IRI Study).
Authors: Ramnaraign Brian Hemendra , Hughes Steven J. , Hitchcock Kathryn , Lee Ji-Hyun , Rogers Sherise C. , Fan Z. Hugh , Allegra Carmen Joseph , Trevino Jose Gilberto , El-Far Ahmad , Russell Karen Bullock , Turk Anita Ahmed , DeRemer David L. , George Thomas J.
Published: January 2021

TPS446

Background: Neoadjuvant treatment for potentially curable pancreatic cancer (PDAC) is increasing in acceptability, but a standard regimen has yet to be established. Multiple studies have demonstrated feasibility and effectiveness of the FOLFIRINOX (5-fluorouracil, leucovorin, oxaliplatin and irinotecan) regimen in the perioperative setting. However, FOLFIRINOX often requires dose modifications, delays and growth factor support due to excessive toxicity which can complicate care delivery when given neoadjuvantly. Liposomal irinotecan injection (Nal-IRI) is FDA approved with a well-tolerated safety profile in relapsed, refractory metastatic PDAC. The current study aims to substitute Nal-IRI for traditional irinotecan in the standard FOLFIRINOX regimen (NALIRIFOX) and to demonstrate safe and effective neoadjuvant delivery. Methods: This phase II, open-label, multicenter single-arm study focuses on patients (pts) with operable PDAC without metastatic disease. Other key eligibility criteria include age ≥18 years, resectability confirmed by multiD GI tumor board (resectable vs. borderline), adequate cardiac, renal, hepatic function and ECOG performance status of 0 to 1. Pts receive NALIRIFOX regimen as per the table below every 2 weeks for four months followed by disease reassessment. Pts who remain surgical candidates will undergo surgical resection within 4 to 8 weeks following last dose of therapy. The primary endpoint is to assess safety and feasibility of regimen in perioperative setting. Secondary endpoints include R0 resection rate, clinical, biochemical and radiological response rate and patient-reported quality of life during treatment as measured by the NCI validated FACT-G scale. Enrollment continues to a maximum of 28 evaluable pts to demonstrate a reduction in historical 30 day postoperative complication rate. Clinical trial information: NCT03483038. [Table: see text]
Phase I study of SEA-CD40, gemcitabine, nab-paclitaxel, and pembrolizumab in patients (pts) with metastatic pancreatic ductal adenocarcinoma (PDAC) (trial in progress).
Authors: Bajor David Lawrence , Gutierrez Martin , Vaccaro Gina M. , Masood Ashiq , Brown-Glaberman Ursa Abigail , Grilley-Olson Juneko E. , Javle Milind M. , Kindler Hedy L. , Gbolahan Olumide B. , Shields Anthony Frank , Zalupski Mark , Schmitt Michael W. , Coveler Andrew L.
Published: January 2021

TPS451

Background: SEA-CD40 is an investigational non-fucosylated, humanized IgG1 monoclonal antibody directed against CD40, a co-stimulatory receptor expressed on antigen-presenting cells (APCs). Activation of CD40 on APCs upregulates cytokine production and co-stimulatory receptors, enhancing tumor antigen presentation to T cells. Preclinical data indicate that treatment of PDAC with chemotherapy in conjunction with a CD40 agonist could enhance antigen presentation and initiate an antitumor immune response (Byrne KT and Vonderheide RH, Cell Rep 2016;15, 2719–2732). A Phase 1 study (SGNS40-001) is evaluating SEA-CD40 monotherapy and in combination with other agents in pts with advanced solid or hematologic malignancies. A cohort is enrolling to evaluate the combination of SEA-CD40, gemcitabine, nab-paclitaxel, and pembrolizumab in PDAC. Methods: The cohort consists of pts with metastatic PDAC who have had no prior therapy for metastatic disease. Pts must be ≥18 years old, with (neo)adjuvant therapy completed > 4 months prior to enrollment; ECOG status ≤1; adequate renal, hepatic, and hematologic function; and measurable disease per RECIST v 1.1 criteria. A standard regimen of gemcitabine and nab-paclitaxel on Days 1, 8, and 15 of each 28-day cycle is administered with SEA-CD40 IV on Day 3. Pembrolizumab is administered every 42 days starting on Day 8. The primary objective is to evaluate antitumor activity; secondary objectives are to evaluate safety and tolerability and SEA-CD40 and pembrolizumab pharmacokinetics. Efficacy endpoints are confirmed RECIST objective response rate per investigator (primary), disease control rate (response or stable disease ≥16 weeks), duration of response, progression-free survival, and overall survival. Disease is assessed every 8 weeks using RECIST and immune-based RECIST (iRECIST). Treatment continues until unacceptable toxicity, progressive disease per iRECIST, consent withdrawal, or study closure, whichever occurs first. Assessment of dose-limiting toxicity will occur initially in groups of 6 pts to identify the recommended phase 2 dose of SEA-CD40 for the cohort. Enrollment to this cohort began in November 2019. Clinical trial information: NCT02376699.
Phase I study of mesothelin-targeted immunotoxin LMB-100 in combination with tofacitinib in persons with pancreatobiliary cancer or other mesothelin expressing solid tumors.
Authors: Pegna Guillaume Joe , Ahmad Mehwish Iqra , Steinberg Seth M. , Peer Cody J. , Figg William Douglas , FitzGerald David JP , Hassan Raffit , Pastan Ira , Alewine Christine
Published: January 2021

TPS452

Background: LMB-100 recombinant immunotoxin consists of a mesothelin-binding Fab for targeting with a modified Pseudomonas exotoxin A payload. Formation of anti-drug antibodies (ADAs) is thought to contribute significantly to limited clinical efficacy of LMB-100 seen in prior clinical trials. Most patients develop clinically meaningful ADAs after 1-2 cycles of LMB-100, resulting in rapid neutralization of LMB-100 during subsequent cycles and undetectable plasma drug levels. Tofacitinib is an oral Janus Kinase-1 and -3 (JAK) inhibitor approved by the FDA for the treatment of rheumatoid arthritis and ulcerative colitis. Pre-clinical studies have shown that tofacitinib can prevent the formation of ADAs against recombinant immunotoxin (Onda et al. Journal of Immunology 2014), and that co-administration of tofacitinib with LMB-100 increases immunotoxin serum half- life in mice and anti-tumor efficacy (Simon et al. JCI Insight 2019). We hypothesize that co-administration of tofacitinib with LMB-100 will prevent or delay the formation of high titer ADAs to LMB-100, such that 2 effective cycles of immunotoxin can be administered to patients. Methods: This phase I clinical trial consists of a dose escalation phase using 3+3 design to determine the maximum tolerated dose (MTD) of LMB-100 that can be administered with tofacitinib in participants (n = 18 max) with mesothelin-expressing solid tumors, followed by a dose expansion phase at the MTD for participants (n = 15) with pancreatic adenocarcinoma or extrahepatic cholangiocarcinoma. The primary objective of the expansion phase is to determine whether co-administration of tofacitinib delays formation of neutralizing anti-LMB-100 ADAs for cycle 2 of treatment as measured by LMB-100 plasma drug levels. A positive outcome will be reached if percent of participants achieving threshold LMB-100 drug levels during cycle 2 increases from 50% to 80% (83.6% probability if >10 of 15 evaluable participants meet this milestone). Plasma drug levels during cycle 3 will also be analyzed as a secondary endpoint. Key inclusion criteria include adults with histologically confirmed previously treated solid tumor malignancies. Participants will receive tofacitinib 10 mg twice daily on days 1-10 and LMB-100 at 65, 100, or 140 mcg/kg on days 4, 6 and 8 of a 21-day cycle. The dose escalation phase has been completed and enrollment onto dose expansion phase is ongoing. Clinical trial information: NCT04034238.
A phase II open-label study in adult and adolescent patients (pts) with advanced solid tumors harboring fibroblast growth factor receptor (FGFR) gene alterations.
Authors: Pant Shubham , Tabernero Josep , Massard Christophe , Iyer Gopa , Witt Olaf , Doi Toshihiko , Qin Shukui , Lu-Emerson Christine , Hargrave Darren R. , García-Corbacho Javier , Little Shonda Marie , Xia Qi , Santiago-Walker Ademi E. , Moy Christopher , Hammond Constance , Sweiti Hussein , Schuler Martin H.
Published: January 2021

TPS480

Background: The pan- FGFR tyrosine kinase inhibitor erdafitinib is approved by the US Food and Drug Administration for adults with locally advanced or metastatic urothelial carcinoma and susceptible FGFR3/2 genetic alterations who have progressed during or after ≥ 1 line of prior platinum-containing chemotherapy. FGFR gene alterations are potential oncogenic drivers that have been reported in many solid tumors in adult and pediatric pts. Because of limited response to standard of care options in pts failing systemic therapy, there is strong rationale to assess the safety and efficacy of erdafitinib in adolescent and adult pts with advanced solid tumors and FGFR alterations. Methods: This phase 2, open-label study (RAGNAR/42756493CAN2002; NCT04083976) will include pts aged ≥ 12 years with histologically confirmed unresectable, locally advanced, or metastatic solid tumors (except urothelial tumors) harboring predefined FGFR mutations or fusions. Eligibility screening includes molecular screening for FGFR alterations by central or local next-generation sequencing assays, and other clinical criteria. Pts will enroll into either a broad panel cohort (BPC) of target FGFR alterations or an exploratory cohort (EC) for FGFR alterations that do not meet criteria for BPC. Approximately 280 pts (BPC, n = 240; EC, n = 40) will be enrolled. The primary efficacy end point is overall response rate (ORR) as assessed by the independent review committee. Secondary end points include investigator-assessed ORR, duration of response, disease control rate, progression-free survival, overall survival, safety, pharmacokinetics, and health-related quality of life. Safety assessments include adverse events, vital signs, electrocardiograms, physical examinations, laboratory tests, performance status assessment, growth assessments in adolescents, and ophthalmologic examination. As of December 2019, pts are being enrolled at ~158 sites in 15 countries. Results of this study will provide efficacy and safety data for erdafitinib across multiple solid tumors with FGFR alterations and evaluate the potential benefit of targeting the underlying altered biology of FGFR irrespective of tumor histology in adult and adolescent pts. Clinical trial information: NCT04083976.
Incidence and Clinical Presentation of Pheochromocytoma and Sympathetic Paraganglioma: A Population-based Study
Authors: Ebbehoj Andreas , Stochholm Kirstine , Jacobsen Sarah Forslund , Trolle Christian , Jepsen Peter , Robaczyk Maciej Grzegorz , Rasmussen Åse Krogh , Feldt-Rasmussen Ulla , Thomsen Reimar Wernich , Søndergaard Esben , Poulsen Per Løgstrup
Published: January 2021

Context

Pheochromocytoma and sympathetic paraganglioma (PPGL) are rare catecholamine-secreting tumors but recent studies suggest increasing incidence. Traditionally, PPGL are described to present with paroxysmal symptoms and hypertension, but existing data on clinical presentation of PPGL come from referral centers.

Objective

We aimed to describe time trends in clinical presentation and incidence of PPGL in a population-based study.

Methods

We conducted a nationwide retrospective cohort study of a previously validated cohort of 567 patients diagnosed with PPGL in Denmark 1977-2015. We collected clinical data from medical records of a geographic subcohort of 192 patients. We calculated age-standardized incidence rates (SIRs) and prevalence for the nationwide cohort and descriptive statistics on presentation for the subset with clinical data.

Results

SIRs increased from 1.4 (95% CI 0.2-2.5) per million person-years in 1977 to 6.6 (95% CI 4.4-8.7) per million person-years in 2015, corresponding to a 4.8-fold increase. The increase was mainly due to incidentally found tumors that were less than 4 cm and diagnosed in patients older than 50 years with no or limited paroxysmal symptoms of catecholamine excess. On December 31, 2015, prevalence of PPGL was 64.4 (CI 95% 57.7-71.2) per million inhabitants. Of 192 patients with clinical data, 171 (89.1%) had unilateral pheochromocytoma, while unilateral paraganglioma (n = 13, 6.8%) and multifocal PPGL (n = 8, 4.2%) were rare.

Conclusion

Incidence of PPGL has increased 4.8-fold from 1977 to 2015 due to a “new” group of older patients presenting with smaller incidentally found PPGL tumors and few or no paroxysmal symptoms.
The pleiotropic functions of autophagy in metastasis
Authors: Marsh Timothy , Tolani Bhairavi , Debnath Jayanta
Published: January 2021

Autophagy is deregulated in many cancers and represents an attractive target for therapeutic intervention. However, the precise contributions of autophagy to metastatic progression, the principle cause of cancer-related mortality, is only now being uncovered. While autophagy promotes primary tumor growth, metabolic adaptation and resistance to therapy, recent studies have unexpectedly revealed that autophagy suppresses the proliferative outgrowth of disseminated tumor cells into overt and lethal macrometastases. These studies suggest autophagy plays unexpected and complex roles in the initiation and progression of metastases, which will undoubtedly impact therapeutic approaches for cancer treatment. Here, we discuss the intricacies of autophagy in metastatic progression, highlighting and integrating the pleiotropic roles of autophagy on diverse cell biological processes involved in metastasis.
Designing and Exploring a Brand-new Strong Superhydrophobic-Conductive Polyaniline-Polysiloxane Composite Anti-corrosion Coating
Authors: Xu Haidong , Ye Qinqin , Chen Nali , Feng Huixia , Qiu Jianhui
Published: January 2021

The superhydrophobic-conductive anti-corrosion mode has attracted much more attention due to the huge economic losses of stainless steel corrosion. Here, a brand-new strong superhydrophobic-conductive polyaniline-polysiloxane (PANIC-RA-POS) anti-corrosion coating was prepared. The internal conductive and dense interpenetrating network polyaniline layer can effectively reduce electrochemical corrosion, the external superhydrophobic polysiloxane layer can effectively decrease chemical corrosion, the adhesive layer obviously improves the binding force of polyaniline and polysiloxane layer, and furthermore, it has excellent protection efficiency, corrosion durability and binding force.
The influence of small field output factors simulated uncertainties on the calculated dose in VMAT plans for brain metastases: a multicentre study
Authors: Clemente Stefania , Falco Maria Daniela , Cagni Elisabetta , Talamonti Cinzia , Boccia Mafalda , Gino Eva , Lorenzini Elena , Rosica Federica , Russo Serenella , Alparone Alessandro , Zefiro Daniele , Fiandra Christian
Published: January 2021

Objectives:

This multicentric study was carried out to investigate the impact of small field output factors (OFs) inaccuracies on the calculated dose in volumetric arctherapy (VMAT) radiosurgery brain plans.

Methods:

Nine centres, realised the same five VMAT plans with common planning rules and their specific clinical equipment Linac/treatment planning system commissioned with their OFs measured values (OFbaseline). In order to simulate OFs errors, two new OFs sets were generated for each centre by changing only the OFs values of the smallest field sizes (from 3.2 × 3.2 cm2 to 1 × 1 cm2) with well-defined amounts (positive and negative). Consequently, two virtual machines for each centre were recommissioned using the new OFs and the percentage dose differences ΔD (%) between the baseline plans and the same plans recalculated using the incremented (OFup) and decremented (OFdown) values were evaluated. The ΔD (%) were analysed in terms of planning target volume (PTV) coverage and organs at risk (OARs) sparing at selected dose/volume points.

Results:

The plans recalculated with OFdown sets resulted in higher variation of doses than baseline within 1.6 and 3.4% to PTVs and OARs respectively; while the plans with OFup sets resulted in lower variation within 1.3% to both PTVs and OARs. Our analysis highlights that OFs variations affect calculated dose depending on the algorithm and on the delivery mode (field jaw/MLC-defined). The Monte Carlo (MC) algorithm resulted significantly more sensitive to OFs variations than all of the other algorithms.

Conclusion:

The aim of our study was to evaluate how small fields OFs inaccuracies can affect the dose calculation in VMAT brain radiosurgery treatments plans. It was observed that simulated OFs errors, return dosimetric calculation accuracies within the 3% between concurrent plans analysed in terms of percentage dose differences at selected dose/volume points of the PTV coverage and OARs sparing.

Advances in knowledge:

First multicentre study involving different Planning/Linacs about undetectable errors in commissioning output factor for small fields.
Social security compliance in times of crisis. Evaluating the factors for non-compliance in the HORECA sectors in Greece
Authors: Koumarianos Evangelos , Kapsalis Apostolos , Avgeris Nikolaos
Published: January 2021

This article studies the impact of the economic recession, labor market deregulation and social security reforms on the level of non-compliance in Greece. It examines the theoretical framework of non-compliance in post-industrial economies, as well as the design of social security systems in preventing contribution evasion. To assess the evolution of non-compliance, especially under conditions of crisis, we examine the results of the INE-GSEE survey on the HORECA sector. According toour research findings, employers follow non-compliant practices in order to maximize their profits, taking advantage of the precariousness of workers, whereas workers accept or collude with non-compliance as a survival tactic within a highly competitive environment. Non-compliance in the Greek labour market appears to be a multi-factor phenomenon that cannot be explained exclusively in terms of a unique perspective.
The child poverty factor as a constraint in a model of overall welfare: The case of Greece
Authors: Leriou Eirini
Published: January 2021

Ιn this paper a specific, specialized and cumulative index is formulated, in a theoretical level, for the measurement of child poverty in Greece. This index is subsequently introduced in a general model of welfare as a constraint and its relation with social solidarity is examined. The creation of an exclusive and polyprismatic child poverty/ welfare index is useful as it helps for a more reliable and exact measurement, in order to take effective policy-measures to address and reduce this phenomenon, which has taken gigantic magnitude in Greece.
Minimum wage in Greece and Southern Europe: Towards a new model for shaping labour relations
Authors: Antonopoulou Maria Georgia
Published: January 2021

The article focuses on the institution of the general minimum wage in Greece and Southern Europe during the economic recession and up to the present day. The economic crisis and the way it was dealt with by European and international institutions led not only to constraints in social expenditure but also restrictive income policies, among other things. Especially in countries that found themselves involved in ‘fiscal adjustment programmes’, like Greece, Spain, and Portugal, the whole of the labour market and labour relations became the arena for radical reforms. The declared targets were increasing flexibility in the labour market, decreasing labour force costs, gradually decentralizing collective agreements, changing the way wages are determined, and strengthening of flexible forms of work. Our study examines the changes in the established method of determining minimum wage in the countries of Southern Europe that were part of fiscal adjustment programmes.
Human Resources for Health in Greece: Current status and the way forward
Authors: Kaitelidou Daphne , Economou Charalampos , Siskou Olga , Konstatakopoulou Olympia , Galanis Petros , Myloneros Thanos , Domente Silviu
Published: January 2021

This paper presents briefly the suggested national human resources for health strategy for Greece, which is based on a rapid assessment of the current situation and drafted around 5 domains/strategic key areas: planning, skills and distribution, retention, governance and government health priorities. It provides an overview of the national context including demographic challenges, health status of the population and emerging health issues as well as health system organizational characteristics and policies with an impact on human resources for health strategy. The main objectives and the guiding principles of the suggested national strategy are explained and proposals for the way forward to successfully implement it are discussed.
Prevalence and determinants of unmet family planning needs among women of childbearing age in The Gambia: analysis of nationally representative data
Authors: Barrow Amadou , Jobe Amienatta , Okonofua Friday
Published: January 2021

Background: Family planning is imperative in the control of population growth by preventing unintended pregnancies and reducing other pregnancy-related risks. However, the effectiveness of family planning is constrained by unmet needs. This study determined the proportion and identify factors associated with unmet family planning needs among women of childbearing age in The Gambia.

Methods: We utilized cross-sectional population-based Demographic and Health Survey (DHS) data from Gambian women aged 15-49 years in 2013. The outcome measured was the total unmet/met need for FP.  The sample comprised 10,233 women aged 15-49 years old. Chi-square test and multivariable logistic regression analysis were used.

Results: Of the 10,233 eligible women recruited in the study, the mean age was 27.4±9.1 years while 67.5% were married. Overall, 17.6% of women reported unmet FP need, of whom 14.0% and 3.6% reported unmet birth spacing and birth limitation needs, respectively. The women's age, region, ethnicity, number of live children, number of household/family members, the optimal number of children, and husband/partners’ desire for the children were found as significant determinants of unmet FP needs. Furthermore, breastfeeding has been identified as the key reason for the non-use of FP in mothers.

Conclusions: The study findings suggest a need to expand FP programs and related strategic communications especially for younger women in order to improve their contraceptive prevalence. Improving women empowerment and accessibility to FP will help to lessen the current trend towards rising unmet needs in The Gambia.
Editorial
Authors: Feijoo Ana Maria Lopez Calvo de , Protásio Myriam Moreira , Portavales Victor , Costa Paulo Victor Rodrigues da
Published: January 2021

Ana Maria Lopez Calvo de Feijoo, Myriam Moreira Protásio, Victor Portavales, Paulo Victor Rodrigues da Costa
"Psicologia Fenomenológica" de Husserl - a (In)compreensão de Psicólogos Brasileiros: Um Estudo Empírico
Authors: Orengo Fabiane Villatore , Holanda Adriano Furtado , Goto Tommy Akira
Published: January 2021

O presente trabalho apresenta resultados obtidos na pesquisa de mestrado intitulada O que o psicólogo compreende por Psicologia Fenomenológica cujo objetivo foi avaliar a compreensão que psicólogos brasileiros possuem sobre fenomenologia e psicologia fenomenológica. Para tanto, foi realizado um estudo de caráter exploratório que teve como instrumento de pesquisa um questionário desenvolvido pelos pesquisadores, no qual foram levantadas questões abertas sobre a compreensão do referido tema, a apropriação dos conceitos na prática profissional e a possibilidade (ou não) de desenvolver uma psicoterapia fenomenológica. Os dados foram analisados utilizando o método qualitativo fenomenológico de Giorgi e Souza. Como resultado, verificou-se que o psicólogo brasileiro compreende a psicologia fenomenológica como uma abordagem da psicologia, e acredita ser possível uma psicoterapia fenomenológica. Conclui-se que o psicólogo brasileiro utiliza diversos conceitos da fenomenologia e da psicologia fenomenológica na descrição de seus fazeres, porém não há correspondência com a proposta de Husserl para a fenomenologia e a psicologia fenomenológica.
Husserl e Gurwitsch sobre a Psicologia da Gestalt: um Estudo sobre o "Sensualismo"
Authors: Santos Hernani Pereira dos
Published: January 2021

Este estudo aproxima fenomenologia e Psicologia da Gestalt tendo por eixo o tema do sensualismo na teoria da percepção. Propõe-se analisar a maneira como a Psicologia da Gestalté avaliada dentro do sistema das investigações fenomenológicas de Husserl e de Gurwitsch. Começa-se por uma breve análise da problemática, confrontando os argumentos de Husserl e de Gurwitsch. Na segunda seção, propõe-se uma análise da teoria da percepção desenvolvida por Husserl em Ideias I. Mostra-se como o conceito de hylē desempenha aí um papel central. Na terceira seção, analisam-se as inovações da fenomenologia desenvolvida por Gurwitsch a partir da interpretação proposta pelo autor a respeito da Psicologia da Gestalt. Mostra-se como, para Gurwitsch, esta teoria psicológica renova a compreensão fenomenológica da organização perceptiva e, por isto, descarta uma determinada interpretação do conceito de hylē com base em um novo conceito de intencionalidade. Ao final, algumas conclusões para as duas linhas argumentativas são propostas.
Encontros e Desencontros entre o Pensamento de Husserl e Heidegger: Fenomenologia em Movimento
Authors: Trzan-Ávila Alexandre
Published: January 2021

O artigo em questão busca discorrer sobre a relevância da fenomenologia de Edmund Husserl no pensamento de Martin Heidegger, em especial em sua obra Ser e tempo de 1927. Mostraremos como as ideias absolutamente paradigmáticas de Husserl se opõem a todo um modo de pensar hegemônico que permanece até os dias de hoje, destacando a noção de intencionalidade que não foi superada ou descartada por Heidegger, mas radicalizada em suas reflexões sobre o existente humano e sua estrutura ontológica originária. De forma a contribuir para o desenvolvimento da compreensão da relação do pensamento desses dois filósofos, ressaltamos que o eixo central deste trabalho consiste em descrever o método fenomenológico husserliano e sua apropriação peculiar no pensamento heideggeriano sobre o existir humano e seu projeto em Ser e tempo, a fim de demonstrar como a fenomenologia de Husserl constituiu pedra angular e imprescindível para a analítica existencial presente em Ser e tempo, sem com isso deixar de apontar algumas diferenças entre os dois pensadores.
A Situação Hermenêutica e a Clínica Psicológica: Caminhos Possíveis
Authors: Andrade Angela Cardoso , Barreto Carmem Lúcia Brito Tavares
Published: January 2021

Este estudo tem como proposição discutir os fundamentos de uma clínica psicológica, numa perspectiva fenomenológica hermenêutica, como situação hermenêutica no quadro da Meta-Ontologia, e segue três momentos. As autoras, ao versarem a clínica como situação hermenêutica com vistas à apreensão e compreensão da facticidade da existência no encontro terapêutico, apontam que seus pressupostos foram delineados inicialmente no Natorp Bericht - Interpretações Fenomenológicas de Aristóteles: indicação da situação hermenêutica. Neste contexto, discutem os três momentos constitutivos fundamentais da situação hermenêutica – Blickstand, Blickrichtung e Sichtweite. Em um segundo momento acompanham o avanço desse projeto em Ser e Tempo, em meio à elaboração da Analítica do Dasein e indicam a situação hermenêutica no quadro da Ontologia Fundamental, por outra forma de explicitação – Vorhabe, Vorsicht, Vorgriff. Consideram que a clínica, como situação hermenêutica em sua extensão meta-ontológica, é concebida pela radicalização da Ontologia Fundamental que propulsa a reviravolta da Ontologia, a partir dela mesma. À guisa de conclusão, consideram a possibilidade de uma extensão clínica meta-ontológica da fenomenologia da existência fáctica e ressaltam a questão metódica do ponto de vista meta-ontológico, com realce para o ponto de vista, a perspectiva e o horizonte de sentido, como caminho a ser percorrido na relação clínica.
Nutritional content and quality of food consumed at recess and lunchtime by 5–8-year-olds
Authors: Stanham Kim , Walton Karen , Bell Alison , Mayland Elizabeth , Parrish Anne-Maree
Published: January 2021

Background:

One in 4 children are overweight or obese and many do not meet the required fruit and vegetable intake of the Australian Dietary Guidelines.

Aim:

To systematically examine the international literature on the nutritional content and quality of meals consumed at recess and lunchtime of primary school children between the age of 5 and 8 years.

Method:

A systematic literature review of peer-reviewed articles published in English with no date restriction placed on publication.

Findings:

Nine studies met the search criteria. Eight studies reported on packed lunches, 4 studies on school prepared lunches and 3 studies on a combination of packed and school prepared food. The majority of food consumed was in excess or short of the countries' recommended guidelines of food groups and nutrients.

Conclusions:

Further study is required to develop a means of improving the problem of not meeting the guidelines of food groups and nutrient consumption.
FIT: A community-engaged approach to health and physical education
Authors: Faigenbaum Avery , Farrel Anne , Perron Tracy , Jakubowski Tami
Published: January 2021

Background:

The purpose of the Smart Nutrition and Conditioning for Kids (SNACK) pilot study was to increase fitness levels and overall health of children aged 7 to 9 years in two elementary schools, one urban and one urban rim. Fundamental Integrative Training (FIT) was incorporated into physical education class and was considered a vital component of SNACK.

Methods:

The FIT intervention was performed twice weekly during physical education class for 8 weeks. Pre- and post-Fitnessgram fitness tests were completed by each child.

Results:

Fitnessgram fitness test scores improved for all fitness tests for both the experimental and control groups in both schools (P<0.05). Significant differences between groups were found in 4 areas: PACER, push-up, curl-ups, and long jump (P<0.05).

Conclusions:

FIT is one example of an interdisciplinary (nursing, health and exercise science students and faculty, elementary school administration and staff) collaborative approach to improving fitness levels with limited time and resources.
Patient Questionnaires in Orthodontics
Authors: Barber Sophy , Shelton Andrew
Published: January 2021

Questionnaires are versatile tools that allow data to be collected from different respondent groups for a range of purposes. This article outlines the use of questionnaires in orthodontics for research, quality improvement and clinical purposes. We highlight the importance of questionnaire design, particularly choosing the type of response to generate useful data and approaches to psychometric testing to measure validity and reliability. Orthodontic-specific questionnaires that have been developed and tested aresummarized.

CPD/Clinical Relevance: Questionnaires are a useful tool for collecting information about patient concerns, experience and outcomes; this information is essential to improve the quality of care. It is crucial that valid and reliable tools are used to optimize the usefulness of information.
Orthodontic Conundrums Part 2: Finishing Cases to a Class III Molar Relationship
Authors: Adam Naeem I , Jowett Adam , Hodge Trevor
Published: January 2021

This is the second article in a series on conundrums in orthodontics. A Class I molar relationship is a frequent aim of orthodontic treatment. There are, however, examples where intentionally finishing to a Class III molar relationship is the more pragmatic and preferable option. Pursuing this approach in the appropriate circumstances may, for example, prevent deleterious consequences to the facial profile or avoid the need for further dental extractions. This article explores the indications for finishing cases to a Class III molar relationship with illustrated clinical cases.

CPD/Clinical Relevance: Dogmatic attempts to deliver Class I molar relationships, in all cases, without consideration of the consequences, have the potential to cause the patient harm. The orthodontist must then consider all possible options available, including those resulting in a Class III molar relationship.
Surprise: a micro-sociological analysis
Authors: Scott Susie
Published: January 2021

This article explores the social and relational aspects of surprise: a reaction to the sudden discovery of unexpected knowledge. Drawing on the micro-sociological perspectives of phenomenology, dramaturgy and symbolic interactionism, I present a five-stage trajectory of this social emotion, charting its emergence, feeling, meaning, responses and function. Surprise emerges from situated encounters when an unexpected incident causes a break in the script. This evokes a subjective experience of flustering and dual consciousness, which separates the actor from their role. The signified meanings of surprise include shifts of biographical identity, changes in power and status, and concerns about the exposure of epistemological naivety. Actors perform expressive gestures of surprise in line with cultural feeling and display rules, using dramaturgical techniques of impression management; these include dramatic realisation and verbal response cries. Team-mates cooperatively enact reparative interaction rituals, such as apologies, token exchange and feigned non-reaction, which restore the normal appearance of a scene. Surprise therefore has the paradoxical quality of being disruptively cohesive. While its immediate expression marks a momentary disturbance, it ultimately functions to maintain interaction order.
45° aligned dual-polarizer for the suppression of signal fading in polarization OTDR
Authors: Wang Xuefeng , Zhao Can , Wu Hao , Liao Ruolin , Shen Li , Chen Wen , Tang Ming
Published: January 2021

A rotating coordinate system model is used to describe the procedure of polarization detection in polarization optical time-domain reflectometry (POTDR), which reveals the relationship of the system response with respect to the initial state of polarization and the direction of the polarizer. On this basis, a 45° aligned dual-polarizer structure is proposed for the suppression of signal fading in the POTDR system. For ease of practical application, an integrated space optics scheme is implemented with the combination of three collimators, one beam splitter, and two polarizers whose principal axes are 45° aligned. Experimental results show that the possibility of signal fading occurrence is reduced from 35.5% in a traditional POTDR down to 6.5% using the proposed scheme.