bluuebunny/crossref_metadata_2025 huggingface dataset:
CULMINATE: A phase II study of cusatuzumab + azacitidine in patients with newly diagnosed AML, ineligible for intensive chemotherapy.
Authors: Trudel Geralyn Carol , Howes Angela J. , Jeste Neelum , Tryon Jeffrey J. , Xiu Liang , Kane Colleen , Nottage Kerri
Published: May 2020

TPS7565

Background: AML, the most common acute leukemia in adults, is a heterogeneous malignancy characterized by uncontrolled clonal expansion of hematopoietic progenitor cells. Median diagnosis age is ~67 yrs. Despite current therapies prognosis is poor with 5-yr OS ~25% for patients (pts) ≥65 yrs. For pts unable to receive intensive chemotherapy, survival rates are worse, indicating a critical need to develop better treatments. CD70 is expressed on >95% of AML blasts harvested from newly diagnosed AML pts but not on normal hematopoietic stem cells nor most normal tissues. Cusatuzumab is a first-in-class, high-affinity anti-CD70 monoclonal antibody with multiple mechanisms of action, including Fc-mediated cytotoxicity with enhanced ADCC and inhibition of CD70/CD27 signaling, resulting in leukemia blast and stem cell cytotoxicity. As cusatuzumab and azacitidine target distinct pathways of myeloblast propagation, a combination may have a synergistic therapeutic effect and overcome treatment resistance. Initial data from a Phase I study (NCT03030612) with cusatuzumab (1–20 mg/kg) + standard dose azacitidine in AML pts ineligible for intensive chemotherapy showed no dose-limiting toxicity and a CR/CRi (CR with partial/incomplete hematologic recovery) in 10 of 12 pts (ASH 2019, Abs #234). This abstract describes a follow-on Phase II study (NCT04023526). Methods: CULMINATE is a 2-part study of cusatuzumab + azacitidine to determine the optimal dose of cusatuzumab (Table). Inclusion criteria: ≥18 yrs with de novo or secondary AML unfit for intensive therapy (≥75 or <75 yrs with a comorbidity [i.e. ≥1 of: ECOG 2, severe cardiac/pulmonary or moderate hepatic impairment]). In Part 1, pts are randomized 1:1 to cusatuzumab 10 or 20 mg/kg (IV, on Days 3 and 17 of each 28-day cycle) + azacitidine (75 mg/m2 SC or IV on Days 1–7). Data will be reviewed after 15, 30 and 50 pts are enrolled into each arm to select the cusatuzumab dose for the Part 2 expansion cohort in which efficacy and safety will be further evaluated. Follow-up continues until death, loss to follow-up or study end. The primary objective is to determine CR rate. Secondary objectives include rate of CRi/CRh, rate of MRD-negativity, ORR, time to and duration of response, pharmacokinetics, immunogenicity, transfusion independence and safety. Enrollment began in Sept 2019 and is currently two-thirds complete. Clinical trial information: NCT04023526 . [Table: see text]
Safety and efficacy of gemtuzumab ozogamicin and venetoclax in patients with relapsed or refractory CD33+ acute myeloid leukemia: A phase Ib study.
Authors: Arain Saad , Christian Sonia , Patel Pritesh Rajni , Sweiss Karen , Parkin Brian , Calip Gregory Sampang , Quigley John G
Published: May 2020

TPS7566

Background: AML is predominantly a disease of the elderly, yet outcomes remain dismal, especially for relapsed/refractory (R/R) AML patients (pts). Gemtuzumab Ozogamicin (GO) is a monoclonal antibody targeting CD33–commonly expressed on AML blasts, and, critically, AML stem cells (LSC)–that is linked to the cytotoxin calicheamicin. Recognized mechanisms of GO resistance include decreased (or aberrant) blast CD33 expression, upregulation of p-glycoprotein (re-exports calicheamicin), and decreased mitochondrial apoptosis. GO-induced apoptosis depends on pro-apoptotic Bax and Bak and is inhibited by overexpression of anti-apoptotic BCL-2 and BCL-XL. Venetoclax (VEN) is a BH3 mimetic, binding BCL-2, dislodging its binding to Bak/Bax, thus facilitating apoptosis. LSC uniquely overexpress BCL-2, however VEN resistance develops rapidly. Hypothesis: VEN targeting of BCL-2 proteins that protect LSC from GO-induced apoptosis will synergistically increase GO efficacy. Correlative studies include pre-treatment AML blast BH3 profiling and CD33 expression (& sequencing for isoforms), MRD measurement at post-therapy timepoints using digital drop PCR technology, and quality of life assessments (EORTC QLQ-C30, FACT-Fatigue). Methods: Single arm, open-label, multi-center (BTCRC), dose-escalation phase Ib study of combination of VEN and GO in R/R AML pts (18-75y), using a 3+3 design. Major eligibility: ECOG 0-2, adequate organ function, CD33+ in ≥ 20% AML blasts, ≤2 lines of prior therapy, no prior use of GO or VEN, no previous VOD, no BMT within 2 months, no CNS disease, and no history of HIV. Induction: 3-day VEN ramp-up to the target dose of 200 (cohort i), 400 (ii), or 600 (iii) mg daily x 28 d, with GO 3mg/m2 infused d 1, 4, and 7. If CR/CRi achieved, pts proceed to BMT if applicable, otherwise, if in CR/CRi (provided ANC > 1000, plts 100K) or PR (regardless of counts), they are consolidated with VEN at the prescribed dose x 28d and GO 3mg/m2 on days 1 and 4 (Cycle 2). If BMT not applicable, and then in CR/CRi or PR (as above), proceed to VEN alone as Maintenance in cycles 3+ until progression or toxicity. The primary endpoint is MTD of VEN with GO. Secondary endpoints include ORR, anti-leukemic activity, characterization of AEs, and estimates of RFS, EFS, and OS. This study is currently open and has to date enrolled 2 pts. Clinical trial information: NCT04070768 .
A phase II/III study of JZP-458 in patients with acute lymphoblastic leukemia (ALL)/lymphoblastic lymphoma (LBL) who are hypersensitive to E. coli-derived asparaginases.
Authors: Maese Luke , Rau Rachel E. , Raetz Elizabeth A. , Lin Tong , Kim Pil , Chandula Reddy , McClung Sherrie , Gray Julie , Choi L. Mi Rim , Loh Mignon L. , Adamson Peter C.
Published: May 2020

TPS7568

Background: L-asparaginase is an important component of ALL therapy and the inability to receive asparaginase secondary to hypersensitivity has been associated with poor patient (pt) outcomes. Alternative options for pts after hypersensitivity reactions are needed. JZP-458 is a recombinant Erwinia asparaginase produced using a novel Pseudomonas fluorescens expression platform that yields an enzyme with no immunologic cross-reactivity to E. coli–derived asparaginases. In a phase 1 study, JZP-458 was well tolerated and maintained adequate (≥0.1 IU/mL) serum asparaginase activity (SAA), a surrogate marker for asparagine depletion, for up to 72 hrs in healthy adults. Methods: This is a pivotal, open-label, multicenter, dose confirmation, and pharmacokinetic (PK) study (NCT04145531) of JZP-458 in pts with ALL/LBL who develop hypersensitivity reactions to a long-acting E. coli–derived asparaginase and have ≥1 course of asparaginase remaining in their treatment plan (Table); 6 doses of JZP-458 will be substituted for each remaining course. Treatment duration will depend on the number of asparaginase courses remaining in the treatment plan. The study has 2 sequential parts: Part A will determine the dose of intramuscular (IM) JZP-458 and confirm safety/efficacy; Part B will explore the dose/schedule of intravenous (IV) JZP-458. Blood samples will be collected to determine SAA levels and pts will be monitored for adverse events. Immunogenicity of JZP-458 will be assessed. Primary objectives are to determine (1) the efficacy of IM JZP-458 measured by the last 72-hr nadir SAA (NSAA) level (≥0.1 IU/mL) during the first treatment course, and (2) the safety/tolerability of IM JZP-458. Secondary objectives are to determine the efficacy (measured by the last 48-hr NSAA level [≥0.1 IU/mL] and the last 48- and 72-hr NSAA levels [≥0.4 IU/mL]), PK, and immunogenicity of IM JZP-458. Exploratory objectives include efficacy, safety, PK, and immunogenicity of IV JZP-458. The trial is active and enrolling. Clinical trial information: NCT04145531 . [Table: see text]
Trial in progress: a phase II, multicenter, single-arm study of zanubrutinib (BGB-3111) in patients with previously treated chronic lymphocytic leukemia/small lymphocytic lymphoma intolerant of prior treatment with ibrutinib.
Authors: Flinn Ian , Shadman Mazyar , Freeman Benjamin Bruce , Chen Dih-Yih , Zhang Xiaoping , Cohen Aileen , Ro Sunhee K. , Huang Jane , Sharman Jeff P.
Published: May 2020

TPS8066

Background: Ibrutinib (ibr), a Bruton tyrosine kinase inhibitor (BTKi), was shown to improve patient outcomes in chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL); however, adverse events (AEs) were the most common reason for discontinuing ibr (50% and 63% of discontinuations in relapse/refractory (R/R) and frontline patients, respectively; Haematologica. 2018:103:874). Zanubrutinib, an approved BTKi for mantle cell lymphoma, was specifically engineered to optimize selectivity. Pooled clinical data from 6 zanubrutinib monotherapy trials in B-cell malignancies (N=682 patients; R/R CLL/SLL [n=91]) suggested that zanubrutinib monotherapy was well tolerated and demonstrated a low rate of treatment discontinuation from AEs (9%; Tam, EHA 2019). Presented here is a trial-in-progress that will evaluate whether zanubrutinib monotherapy may serve as a therapeutic option for patients with CLL/SLL who have become ibr intolerant. Methods: The ongoing phase II, multicenter, US, single-arm, open-label study (NCT04116437, BGB-3111-215) will evaluate zanubrutinib monotherapy (160mg twice daily) as a treatment option for patients with CLL/SLL intolerant to prior ibr treatment. Approximately 60 patients will be enrolled from ~30 community medical centers. Key inclusion criteria include CLL/SLL requiring treatment per International Workshop on CLL criteria ( Blood. 2018;131:2745) before ibr therapy, intolerance to ibr (defined as an unacceptable AE for which, per investigator’s opinion, ibr treatment should be discontinued despite optimal supportive therapy), resolution of ibr-related AEs to grade ≤1 or baseline, and an ECOG PS 0-2. Key exclusion criteria include having an intervening cancer therapy between ibr and zanubrutinib, a documented disease progression during ibr treatment up to the time of enrollment, and a history of central nervous system (CNS) hemorrhage. The primary endpoint is frequency and severity of protocol-specified treatment-emergent AEs (diarrhea, myalgia, muscle spasm, arthralgia, hypertension, fatigue, rash, atrial fibrillation, and hemorrhage excluding CNS hemorrhage). The secondary endpoints include overall response rate, progression-free survival, and patient-reported outcomes. An exploratory endpoint was added to evaluate clinical effects (physical activity, treatment-related symptoms, and quality of life) using a smartphone app. Recruitment is ongoing. Clinical trial information: NCT04116437 .
An intergroup collaboration for advanced stage classical Hodgkin lymphoma (cHL) in adolescents and young adults (AYA): SWOG S1826.
Authors: Castellino Sharon M. , LeBlanc Michael Leo , Herrera Alex Francisco , Parsons Susan K. , Punnett Angela , Hodgson David C. , Rutherford Sarah C. , Khan Nadia , Constine Louis S. , Davison Kelly , Prica Anca A. , Friedberg Jonathan W. , Kelly Kara M.
Published: May 2020

TPS8067

Background: Treatment for pediatric cHL varies considerably from that in adult cHL. Hence there are gaps in risk prediction and optimal therapy for de-novo advanced stage disease across the adolescent and young adult (AYA) age spectrum. Early access to novel agents for AYA could be facilitated via collaboration with adult research groups through the U.S. National Cancer Institute’s National Clinical Trials Network (NCTN). The PD-1 inhibitor Nivolumab (Nivo) has safety and efficacy in relapsed and refractory disease in children and adults, but has not been evaluated in de-novo disease to date. Methods: North American cooperative group lymphoma chairs, Cancer Therapy Evaluation Program (CTEP) representatives and patient advocates met to establish consensus on the comparison arms and study design, based on recent historical approaches across adult and pediatric groups. Study champions were identified across North American cooperative groups and include expertise in imaging, radiation oncology, biology and patient-reported outcomes. A therapeutic study was designed with the primary aim being to compare progression-free survival with novel targeted agents in advanced stage cHL. S1826 (NCT03907488), led by SWOG Cancer Research Network, opened to accrual in July 2019. Eligibility criteria include age > 12 years, and Stage III or IV cHL. Patients are randomized (1:1) to 6 cycles of either Nivo-Adriamycin, Vinblastine, Dacarbazine (AVD) or Brentuximab vedotin (Bv)-AVD. Enrollment is stratified by age, baseline International Prognostic Score, and provider intent to use involved site radiation therapy (ISRT). Protocol-prescribed ISRT is response-adapted, based on end of therapy imaging. The primary endpoint is a comparison of progression-free survival between arms. Secondary clinical endpoints include comparison of: overall survival, metabolic response at the end of therapy, physician-reported adverse events, patient-reported adverse events, and health-related quality of life (overall, and specific to fatigue and neuropathy). This unique intergroup collaboration demonstrates the process and the feasibility of consensus study designs toward early adoption of targeted therapies and harmonization of treatment approaches for AYA populations. Clinical trial information: NCT03907488 .
A phase II study of MT-3724, a novel CD20-targeting engineered toxin body, to evaluate safety, pharmacodynamics, and efficacy in subjects with relapsed or refractory diffuse large B-cell lymphoma.
Authors: Diaz Duque Adolfo Enrique , Perekhrestenko Tetiana , Musteata Vasile , Zodelava Mamia , Guthrie Troy H. , Strack Thomas , Burnett Christine , Wilson Sarah , Waltzman Roger J. , Baetz Tara D. , Persky Daniel O.
Published: May 2020

TPS8074

Background: Engineered toxin bodies (ETBs) are comprised of a proprietarily engineered form of Shiga-like Toxin A subunit (SLT-A) genetically fused to antibody-like binding domains. ETBs work through novel mechanisms of action and are capable of forcing internalization, self-routing through intracellular compartments to the cytosol, and inducing potent cell-kill via the enzymatic and permanent inactivation of ribosomes. MT-3724 represents a novel ETB modality comprised of an anti-CD20 single-chain variable fragment genetically fused to SLT-A. It is capable of efficient internalization once bound to CD20 and can induce potent direct cell-kill via enzymatic ribosome inactivation. MT-3724 is currently being studied in three ongoing Phase 2 studies for relapsed or refractory diffuse large B-cell lymphoma (r/rDLBCL). Methods: The primary objective of this single-arm, Phase 2 study (NCT02361346) is to determine the efficacy of MT-3724 monotherapy in r/rDLBCL based on overall response rate (ORR), defined as the proportion of subjects with a complete/partial response according to the Lugano criteria, as assessed by independent, central review. Key secondary objectives include safety, progression-free survival, investigator‐assessed ORR, duration of response, overall survival, and pharmacodynamics. Adverse events will be assessed and documented according to Common Terminology Criteria for Adverse Events version 5.0. Key eligibility criteria include adult subjects with histologically confirmed, r/rDLBCL, with ≥2 prior standard of care systemic NHL treatment regimens, and ≥1 measurable lesion. As rituximab and other CD20-targeting antibodies compete with MT-3724 for the same CD20 domain, minimum washout periods from these agents must be observed. Subjects remain eligible post stem cell transplant or chimeric antigen receptor T-cell therapy. Subjects will receive 50 µg/kg MT-3724 IV over 1 hour on Days 1, 3, 5, 8, 10 and 12 of a 21-day treatment cycle. The anticipated sample size is N = 100. Interim analyses will be performed to confirm minimum efficacy thresholds based on the encouraging data observed in the completed phase 1 portion of the study [Hamlin et al. Blood 2019;134(Suppl 1):4098]. Multiple global sites are enrolling subjects. Clinical trial information: NCT02361346 .
Phase I study of radiotherapy (RT) & durvalumab in relapsed/refractory diffuse large B-cell lymphoma (DLBCL) & follicular lymphoma (FL): The RADD study.
Authors: Hawkes Eliza Anne , Manos Kate , Chong Geoffrey , Palmer Jodie , MacManus Michael Patrick , Keane Colm , Scott Andrew Mark , Shortt Jake , Ritchie David , Churilov Leonid , Johnston Laura , Witkowski Tom , Barraclough Allison Anne , Lee Sze Ting , Lin Wendi , Koldej Rachel , Khor Richard
Published: May 2020

TPS8075

Background: Most DLBCL & FL responds well to first line treatment, yet relapsed disease outcomes are poor. PD1/PDL1 inhibitors yield high response rates in some lymphomas, but single agent therapy in heavily pre-treated pts are disappointing. RT stimulates anti-tumor immunity through several mechanisms and may enhance response to immune checkpoint inhibition (ICI). Concurrent ICI & RT is synergistic in preclinical studies & solid tumors, improving local & distant (abscopal) response. RT to multiple disease sites may broaden the spectrum of tumor antigen release and overcome clonal variation between disease sites to further augment the immune response. Methods: RaDD (NCT03610061) is a phase I, 3+3 dose escalation study to determine the safety profile of escalating dose & number of sites of RT in combination with Durvalumab (anti-PD-L1 antibody) in RR DLBCL & FL. Eligible pts (i.e. ≥1 prior therapy, ineligible for auto-SCT, no contraindication to PDL1i) receive 5 fractions of external beam RT to target site(s). 5 RT dose & site levels are included (dose range 2.5Gy-20Gy to 1-3 sites). Durvalumab 1500mg IV commences day 2 of RT and continues 4-weekly until confirmed disease progression. The DLT period is 28 days from start of RT. Primary endpoint is the recommended phase two dose (RP2D) of RT in combination with durvalumab. Secondary endpoints include response rates, PFS & OS. Correlative studies will examine the tumour-immune system interaction; an exploratory PET substudy with novel tracers for durvalumab (89Zr-Durvalumab) & CD8+ T cells (89Zr -Df-IAB22M2C) will also be performed. Projected enrollment for determination of maximum tolerated dose (MTD) & RP2D is 6-30 pts pending toxicity. Recruitment will continue to 36 pts for secondary endpoint analysis. 9 pts are enrolled across cohorts 1-3 to date. Clinical trial information: NCT03610061 .
Trial in progress: Neoadjuvant immune checkpoint blockade in resectable malignant pleural mesothelioma.
Authors: Reuss Joshua E. , Sepesi Boris , Rolfo Christian Diego , Zahurak Marianna , Anagnostou Valsamo , Smith Kellie Nicole , Cottrell Tricia , Stein Julie E. , Illei Peter Bela , Taube Janis M. , Rosner Gary L. , Murray Joseph Christopher , Nakajima Erica C. , Voong K Ranh , Hales Russell K. , Yang Stephen , Battafarano Richard James , Friedberg Joseph , Tsao Anne S. , Forde Patrick M.
Published: May 2020

TPS9078

Background: While the role of surgery in limited-stage (stage I-III) malignant pleural mesothelioma (MPM) is controversial, many centers have adopted an aggressive tri-modality approach incorporating (neo)adjuvant chemotherapy, surgical resection and radiotherapy. Despite this, most patients relapse and die from their disease. Immune checkpoint blockade (ICB) has shown promise in advanced MPM, but the mechanisms of response and resistance remain elusive. Improving the mechanistic understanding of ICB in MPM while concurrently optimizing the treatment strategy for limited-stage MPM are two urgent unmet needs. This multicenter multi-arm phase I/II study seeks to evaluate the safety and feasibility of neoadjuvant ICB in resectable MPM, incorporating novel genomic and immunologic analyses to deliver mechanistic insight into the biology of ICB in MPM. Methods: Patients with surgically resectable stage I-III treatment-naïve epithelioid or biphasic MPM receive neoadjuvant treatment with nivolumab every 2 weeks for 3 doses with or without 1 dose of ipilimumab (arm A: nivolumab monotherapy; arm B: nivolumab + ipilimumab). After macroscopic complete resection, patients receive optional investigator-choice adjuvant chemotherapy +/- radiation. Following this, patients will receive up to 1 year of adjuvant nivolumab. Feasibility and safety are co-primary endpoints of this study with feasibility defined by a delay in surgery of ≤24 days from the preplanned surgical date and safety defined by adverse events according to CTCAE v5.0. Bayesian-designed stopping rules have been implemented for feasibility and safety. Secondary endpoints include assessment of pathologic response and radiographic response using RECIST 1.1 for MPM. Correlative analyses will be performed on tissue specimens obtained pre- and post-ICB, as well as blood obtained pre, during, and post-ICB. Key correlates include multiplex immunofluorescence and longitudinal ctDNA assessment. Whole exome sequencing, T-cell receptor sequencing, and the MANAFEST functional neoantigen assay will be utilized to identify neoantigen-specific T-cell clonotypes and track these clonotypes temporally (during/post ICB) and spatially (across immune compartments). Single-cell RNA sequencing will be used to characterize the functionality of expanded T-cell clonotypes. Accrual to arm B will commence following complete accrual to arm A with a planned total enrollment of 30 patients. This study is open with 1 patient enrolled at the time of submission. Clinical trial information: NCT03918252.
Randomized phase II study of canakinumab (CAN) or pembrolizumab (PEM) as monotherapy or in combination as neoadjuvant therapy in patients (Pts) with surgically resected (Stage IB-IIIA) non-small cell lung cancer (NSCLC): CANOPY-N.
Authors: Mok Tony S. K. , Garrido Lopez Pilar , Kim Edward S. , Arslan Cagatay , Pujol Jean-Louis , Song Yuanbo , Blin Cecile , Rodrik-Outmezguine Vanessa , Mookerjee Bijoyesh , Passos Vanessa Q. , Lee Jay M.
Published: May 2020

TPS9626

Background: Complete surgical resection is the standard treatment (tx) for pts with stage I-IIIA NSCLC. 5-year survival rates range from 19-50%, with most pts dying from distant recurrence. Neoadjuvant or adjuvant chemotherapy improves overall survival (OS) by only 5% in pts with NSCLC, and new tx options are needed. Preliminary data with PD-1 or PD-L1 inhibitors as neoadjuvant therapy has shown major pathologic responses (MPR) or pathologic complete responses (pCR) in pts with early stage NSCLC. CANTOS study demonstrated reduced incidence of NSCLC and decreased lung cancer-related mortality with CAN (IL-1β inhibitor) versus placebo, in a dose-dependent manner for pts with atherosclerosis. In pre-clinical NSCLC humanized models, tx with CAN±anti PD-1 inhibitor could lead to anti-tumor activity. Combination of CAN and PEM is expected to enhance the efficacy of PD-1 inhibition by inhibiting dysregulated inflammation in tumor microenvironment. Based on available evidence, CANOPY-N study was designed to evaluate effect of CAN and PEM as monotherapy or in combination as neoadjuvant tx for pts with resectable NSCLC. Methods: CANOPY-N (NCT03968419) is a phase II, randomized, open-label study evaluating effect of CAN or PEM monotherapy or in combination as neoadjuvant tx in resectable NSCLC pts. Histologically confirmed stage IB-IIIA, tx-naive, ECOG PS 0-1 NSCLC pts eligible for surgery and with a planned surgical resection in approximately 4-6 weeks (after 1st dose of study tx), are eligible to participate. An archival (if obtained up to 6 months before 1st day of tx) or new biopsy is required. Approximately 110 pts will be randomized in 2:2:1 ratio (stratified by histology [squamous/non-squamous]) to one of the tx arms to receive a total of 2 doses (200 mg Q3w) of CAN alone (n = 44) or in combination with PEM (n = 44) or PEM (n = 22) with safety follow-up up to 130 days from last study drug dose. Primary endpoint is to determine MPR rate (≤10% of residual viable tumor cells at time of surgery), secondary endpoints include determination of ORR, MPR rate based on local review, surgical feasibility rates, anti-drug antibodies incidence and PK parameters. Clinical trial information: NCT03968419 .
Pulmonary Function in Patients With Multiple Endocrine Neoplasia 2B
Authors: Fuller Sarah , Del Rivero Jaydira , Venzon David , Ilanchezhian Maran , Allen Deborah , Folio Les , Ling Alexander , Widemann Brigitte , Fontana Joseph R , Glod John
Published: May 2020

Context

Multiple endocrine neoplasia type 2B (MEN2B) is a rare cancer predisposition syndrome resulting from an autosomal-dominant germline mutation of the RET proto-oncogene. No prior studies have investigated pulmonary function in patients with MEN2B.

Objective

This study characterized the pulmonary function of patients with MEN2B.

Design

This is a retrospective analysis of pulmonary function tests (PFTs) and chest imaging of patients enrolled in the Natural History Study of Children and Adults with MEN2A or MEN2B at the National Institutes of Health.

Results

Thirty-six patients with MEN2B (18 males, 18 females) were selected based on the availability of PFTs; 27 patients underwent at least 2 PFTs and imaging studies. Diffusion abnormalities were observed in 94% (33/35) of the patients, with 63% (22/35) having moderate to severe defects. A declining trend in diffusion capacity was seen over time, with an estimated slope of −2.9% per year (P = 0.0001). Restrictive and obstructive abnormalities were observed in 57% (20/35) and 39% (14/36), respectively. Computed tomography imaging revealed pulmonary thin-walled cavities (lung cysts) in 28% (9/32) of patients and metastatic lung disease in 34% (11/32) of patients; patients with metastatic lung lesions also tended to have thin-walled cavities (P = 0.035).

Conclusions

This study characterized pulmonary function within a MEN2B cohort. Diffusion, restrictive, and obstructive abnormalities were evident, and lung cysts were present in 28% of patients. Further research is required to determine the mechanism of the atypical pulmonary features observed in this cohort.
Logistics Providers As Integrators of Intelligent Supply Chain Systems: an Innovative Aspect
Authors: Kamchatova E.
Published: May 2020

This article is devoted to determining the role and place of logistics providers in managing international supply chains, analyzing their classifications and transforming business models in supply chains in the context of active e-Commerce development, as well as identifying specific features of system and virtual integrators of supply chains that can significantly increase the level of logistics service.

Active use of e-Commerce leads to a significant reduction in response times to demand and encourages supply chain managers to constantly search for new solutions and innovative technologies that enable companies involved in the logistics chain to effectively interact with each other and jointly respond to changing consumer demands. In some cases, we are talking about creating new approaches and replacing existing technologies aimed at achieving the set results in terms of speed and flexibility in choosing options to meet consumer demand. Thus, the analysis allows us to state that logistics mediation as a special sphere of business activity has passed the stage of formation. The prerequisites for its improvement are primarily related to the implementation of the strategy of innovative balanced development of the national economy and further development of the logistics services market. Starting with the 3PL model, all logistics service providers actively use information and communication technologies, work in both retail and e-Commerce formats, and develop on the principle of system outsourcing, creating significant added value for their customers by saving time and resources, sharing responsibilities, and responding quickly to changes in consumer preferences. We can state with confidence that if earlier logistics was considered as a function of providing business, now it determines the system way of doing business and its innovative technologies.
Share Repurchase As the Instrument of the Management of the Capital of the Company
Authors: Galanov Vladimir , Galanova A.
Published: May 2020

The joint-stock company is a participant in the primary stock market, primarily as an issuer of shares and bonds. However, in the event of the repurchase of its shares, the joint-stock company may also act as a specific participant in the secondary market. When buying its own shares, the joint-stock company is turning into a specific type of investor and speculator in the stock market, and the shares it purchases form a redemption issue portfolio that requires proper management, as well as an investment portfolio. Share repurchases may have economic, “technical” and even political and social reasons. Repurchased shares may relate to a group of treasury shares or a group of quasi-treasury shares. The existence of quasi-treasury shares means that there is an opportunity in which it is not external shareholders who control the joint-stock company but the company's top management, which is no longer under the control of the shareholder group.
Advance care plans for patients in general practice
Authors: Frankova Helena
Published: May 2020

The coronavirus pandemic has led national leaders to encourage providers to put advance care plans in place for older people, those who are frail and people with other serious conditions. We examine why this is important and how this is addressed
Combating the collateral damage of COVID-19
Authors: Dempster Helen
Published: May 2020

During the COVID-19 pandemic, many patients have been fearful of seeking medical attention in fear of contracting coronavirus or being a ‘burden’ on the overstretched NHS, meaning even treatable illnesses could escalate into an avoidable situation
Feline idiopathic cystitis: what to suggest
Authors: Poole Amelia
Published: May 2020

This paper reviews the available evidence for the treatments for feline idiopathic cystitis (FIC). The true pathophysiology of FIC can vary between patients, and includes intrinsic abnormalities, increased sensitivity to stressors, reduced nerve sensitivity or an abnormal sympathoneural outflow. Current treatment for FIC involves a variety of medications including analgesia, antibiotics, nutraceuticals, antispasmodics, environmental modification and diet alteration. Environmental changes have been shown to reduce the occurrence of symptoms; however, the trials indicating this were uncontrolled because of the number of changing variables. Evidence for the use of medications is lacking, identifying the need for further research in this area.
Anaesthetic management of paediatric and neonatal patients
Authors: Thurston Ashleigh
Published: May 2020

This article aims to highlight the key physiological differences in the paediatric patient in comparison to the adult and how they may impact anaesthetic management in practice from pre-operative considerations through to recovery. The critical importance of communication within the veterinary team is highlighted to ensure successful outcomes and reduce the risk of mortality. Potential complications are discussed as they are inherent to anaesthesia, however early identification and intervention can help ensure patient safety. Although paediatric and neonatal anaesthesia may be challenging, it can also be incredibly satisfying for the registered veterinary nurse (RVN) as specific nursing care needs to be provided throughout the peri-operative period to facilitate a smooth anaesthetic and recovery.
VIABILIDADE ECONÔMICA DO USO DE TRATOR/IMPLEMENTOS AGRÍCOLAS NA CONSTRUÇÃO DE TERRAÇOS
Authors: Ribeiro Ramos Cássio André , Souza Luiz Henrique , Oliveira Flávio Gonçalves
Published: May 2020

O objetivo deste trabalho foi analisar os custos operacionais do uso da mecanização agrícola na construção de terraços, bem como a viabilidade econômica da compra. O trabalho foi realizado no município de Montes Claros-MG. Os Custos Operacionais foram avaliados considerando a possível implantação de três terraços: Manghum, Nichols e Base Larga. Adotou-se um arado fixo de três discos para o tipo Manghum, um arado reversível de três discos para o tipo Nichols e um terraceador para o de Base larga. Mesmo com maior custo horário (R$ h-1), o terraceador proporcionou menor custo total (R$ terraço-1) e consequentemente maior número de terraços construídos por hora, devido à maior eficiência deste implemento. O Ponto de Nivelamento demonstrou que para o terraço tipo Manghum será viável adquirir o trator e arado fixo, se o número de horas trabalhadas superar 219,3 horas anuais, no terraço tipo Nichols será viável adquirir o trator e arado reversível com número de horas trabalhadas superior a 247,7 horas anuais e o terraço tipo Base Larga será viável adquirir o trator e terraceador, com número de horas superior a 167,8 horas anuais.
El cooperativisme rabassaire al Penedès durant el primer terç del segle xx
Authors: Soler-Becerro Raimon
Published: May 2020

Aquest article es proposa demostrar com el cooperativisme agrari d’esquerres, que aquí anomenarem rabassaire, es va difondre durant el primer terç del segle XX amb intensitat per bona part del territori. Les cooperatives havien estat la principal forma d’organització del moviment rabassaire abans que es creés la Unió de Rabassaires el 1922. La majoria es van consolidar pel seu caràcter multifuncional —cooperativa de consum i agrària, mutualitat, sociabilitat i reivindicació—, però també per una gestió econòmica que en garantia la continuïtat i que va ser truncada de soca-rel pel resultat de la Guerra Civil.
Warum hat es das Erbbaurecht so schwer? – Zur Erhöhung der Akzeptanz von Erbbaurechten durch mehr Marktgerechtigkeit
Authors: Löhr Dirk , Braun Oliver
Published: May 2020

Erbbaurechte werden in den letzten Jahren zwar wieder verstärkt verwendet, führen aber immer noch ein Nischendasein. Bei Erbbaurechten findet eine Aufspaltung der Eigentumsrechte an der Immobilie statt. Hierdurch entstehen einerseits zusätzliche Kontroll- und Durchsetzungskosten, andererseits auch Eingriffe in die Verfügungsrechte des Erbbauberechtigten. Beides führt zu Wertabschlägen, mit denen Volleigentum nicht belastet ist. Dies belastet sowohl die Rendite als auch die Möglichkeiten, bezahlbaren Wohnraum über Erbbaurechte zur Verfügung zu stellen. Hinzu kommen Nachteile bei der Veräußerbarkeit und der Beleihbarkeit von Erbbaurechten. Auf der anderen Seite können Erbbaurechte als ein Instrumentarium zur Reallokation von Investitionsrisiken auf den Erbbaurechtnehmer verstanden werden. Marktgerechtigkeit vorausgesetzt, sinken die Renditeforderungen der Erbbaurechtgeber stärker ab, als die Renditeforderungen der Erbbaurechtgeber ansteigen. Hierdurch entstehen u. U. beträchtliche Diskontierungsgewinne, die bei Volleigentum nicht generiert werden und die eine Überkompensation der Nachteile des Erbbaurechts bewirken können. Allerdings erlaubt es die Art und Weise, wie in Deutschland Erbbaurechte angewandt werden aber nicht, diesen potenziellen Mehrwert tatsächlich auszuschöpfen. Es werden Modelle aufgezeigt, die diese Anwendungsprobleme auf einfache Weise beheben.
A magyarországi K+F helyzete, európai uniós tükörben
Authors: Balogh Sándor
Published: May 2020

The situation and efficiency of R & D activities in Hungary were analysed with the use of Eurostat and Central Statistical Office data. The conclusion was drawn that the system of indexes used and published officially is hardly suitable for presenting the existing problems and for carrying out strategic analyses. The analysis of the official data leads to the conclusion that it would be advisable to use long statistical time series and to apply indexes showing specific development more extensively. The situation of R & D in Hungary is presented in the paper from this approach. We have found that certain problems hindering R & D in Hungary, such as the insufficient concentration of researches, the insufficient proportion of business-like researches and researches promising direct economic benefits in general, the problems of the distribution of research investments between fields of science etc., could not be solved in the period after the change of the regime, either. In many respects the current situation of R & D is definitely worse than before the change of the regime, first of all as concerns the financing of R & D. The dominance of publication-centeredness as one of the approaches indicating efficiency may overshadow the fundamental duality in the relationship of R & D with economy, namely that economy should be not only the source but also the primary beneficiary of R & D activities.
Egy mezőgazdasági értékesítő szövetkezet stratégiája
Authors: Kis Mária
Published: May 2020

In Hungary, the role of collection farms, wich have numerous forms in increasing due to agricultural policy inspiring fusions. Producer Organisations have to be emphasized among collective farms because under the control of European Union's vegetable and fruit market, subsidy is paid through them. In all fruit an vegetable growing regions of Hungary Growing and Trading Organizations have come into existents, so the geographical cover is nearly complete. There are 58 Producer Organizations currently in Hungary, In 2007 the turnover of product issue in the sector was HUF 179 billion, The fruit and vegetable growing organisations and groups turnover was HUF 35 billion. Their total turnover has been stagnating at about 15% of the total product issue in the sector. Mórakert Cooperatives's turnover runs to 15-20% of Growing ar.d Trading Organisation's totai turnover. In my thesis deal with Mórakert Fruit and Vegetable Producer Organization, which is the biggest one in Hungary, its products can be found on the shelves of most domestic supermarket chains.
Adatbiztonság a Mérnöki Kar személyi számítógépein
Authors: Hampel György , Fabulya Zoltán , Nagy Elemérné
Published: May 2020

It is very important to protect the digitally stored intellectual product in an organization where education and research is the main activity. We have asked our colleagues at the Faculty of Engineering to take part in a survey about data protection. Our findings were: - Only colleagues, who use computers regularly, sent back the questionnaire via email. - The most used operating system is Windows XP Pro. Linux and Windows Vista are only used on a few machines. - The frequency of hardware and software failures (blue screen of death, freezing, virus infection, data loss, etc.) indicate that more frequent maintenance is required. - The data protection provided by the operating system or other software (firewall, virus scanner, etc.) is more commonly used than hardware based protection (ups, hard disk data protection card, etc.) - The autoupdate feature is used to update the software, manual update is not typical. - Nearly all of our colleagues could give a correct estimate of the size of the programmes and documents or other data. So they know how much storage they need to store their files and to make backups. - Two third thinks that he or she can make backup copies and can also restore them. On the other hand most of them do not know whether there is a backup programme installed on the PC (although Windows XP has one). - CD, DVD and USB flash drives are used by half of the colleagues to store backup copies. Some use a separate hard disk or a separate partition for the backup. Almost half of them said that they make copies themselves, but the other half thinks that the backup is made automatically by the programmes or they have no clue at all. - Half of the colleagues think that restoring a complete system from a backup requires more time than installing and setting up all the software. This indicates that the knowledge about backup and restore is mostly theoretic and the computer users at our faculty have no real experience in backing up and restoring.
A kutatás-fejlesztés regionális különbségei Magyarországon
Authors: Keczer Gabriella
Published: May 2020

A tudásalapú gazdaságban a kutatás-fejlesztés az országok és azokon belül az egyes régiók fejlődésének, versenyképességének egyik legfontosabb motorja. A statisztikai adatokból azonban kiderül, hogy Magyarországon a K + F tevékenységet; a kutatói létszámot, a K + F ráfordításokat és a tudományos outputot is tartós Budapest-központúság jellemzi. A fővárosin kívüli régiókban pedig csak az egyetemmel rendelkező megyékben van számottevő tudományos tevékenység. Az ország tudományos „vízfejűségének" több káros következménye is van; melyek nemzeti és regionális szinten is visszafogják a fejlődést. A vidéki egyetemi városok tudományos potenciálja nem éri el azt a kritikus tömeget, amelyre tudásalapú regionális gazdasági fejlődés lenne építhető, (az) egyetlen centrum pedig nem képes produkálni azt a tudományos outputot, amely a nemzetgazdaság innovációra, hozzáadott értékre épülő szerkezetváltását biztosítaná. A kutatói kapacitással alig-alig rendelkező térségeknek esélyük sincs innovatív cégek megtelepítésére; így ezekben a perifériális szerepkörbe kényszerülő területeken a növekedés és az életszínvonal is tartósan alacsony marad.
A fűszerpaprika, mint hagyományos magyar termékünk fogyasztási szokásainak elemzése
Authors: Panyor Ágota
Published: May 2020

The certain countries of the European Union can preserve their competitiveness only in that manner if the member states can keep their individuality and identity on a long distance. For the sake of the cause, it is important to provide most of our unique, traditional hungarian products with communal trademark to protect our values and to reserve the traditional technologies. The produce of Red Paprika of the landscape district of Szeged and Kalocsa is under communal trademark proccess and hopefully it will get it in this year.
A földvásárlás és birtoklás főbb kérdései Magyarországon
Authors: Vincze-Lendvai Edina
Published: May 2020

In Hungary the land-purchasing is not too active business. The prices are have been growing since 2004, but they are not really high. After the EU-accession the new states got moratórium, until 2011. In the study I have analyzed the situation of the Hungárián regulation of the land-owning, the change of the land- price, the alteration of the land-market after 2004.1 have examined and compared the example of the other unión states.
A kiváló csapat főbb jellemzői
Authors: Gulyás László , Turcsányi Enikő
Published: May 2020

Nowadays the "team", "team-works" "team-player" and "team-buildings" are the very important area of management studies. Our paper examines small pieces of this area, we examine the features of excellent team. One author of this paper is psychologist, the other one is HR-manager, both of them investigate the features of excellent team from their point of view.
Az első jugoszláv állam felbomlásához vezető strukturális problémák
Authors: Gulyás László
Published: May 2020

Yugoslavia was born twice (1918, 1945) and split twice (1941, 1991) during the short - 91 years - of its history, thus we think it is worth to analyze the reasons of those splits. We are concerned that the reasons - first of all the regional differences - causing the split the first Yugoslav state (1918-1941). In our paper we analyze how first Yugoslav state tried to overcome regional differences, and how it led to the split of the state.
A közösségfejlesztés lehetőségei a Kiskőrösi kistérségben
Authors: Panyor Ágota
Published: May 2020

The Great Depression has his effect felt powerfully on Hungary in our days. I believe that the community development wich one was alredy used on many fields int he world with succes might report the solution in our homeland as well. I will introduce the micro-region of Kiskőrös. The people's living in this area gets out mainly from the agrarian section, fruits, grapes and naturelly the winery. Unfurtunately, by today considerable decline can be observed on that place. I will try to find out the real reasons, according to the community develpoments' method I have made a research among the viticulturist int he form of oral asking.
Balatonszárszó marketing szempontú vizsgálata
Authors: Vincze-Lendvai Edina
Published: May 2020

Near the Laké Balaton there are a lot of little or bigger villages. I chose one of their numbers: Balatonszárszó, to make a marketing analysis. First I made a secondary research, and then I made an interview with the mayor of the township. On the basis of these results I made a SWOT-analysis of Balatonszárszó. The main establishment are: the developing village is a perfect summer resort for people who like a peaceful, quiet place.
Mezőgazdasági munkavégzés és munkakörülmények a sajtó tükrében
Authors: Móré Mariann
Published: May 2020

In the last fifty years there were three major changes in the life of the Hungarian province, that has meant a significant challenge and required extraordinary adaptibility. Within one generation, working conditions, social relationship and social values of the provincial population have completely changed. Many social studies deal with presenting these transformations. The non-expert newspaper readers, however, get informed from the mass media, and not from the white papers of the sociologists; so, they evaluate the agricultural potential, situation and development based on these inputs. In my current study, I am looking for the answer on what kind of tendentious concerted occurence do readers use to form their opinion about the working conditions and the jobs of the farmers. Of course, besides my study, a conclusion about the agriculture can also be made based on other areas of mass media. My aim with the current study was to outline a trend using 700 articles about agriculture.
Hőkezelési folyamat modellezési adatainak előkészítése, elemzése húskonzerv-gyártás gázfogyasztásának optimálásához
Authors: Fabulya Zoltán
Published: May 2020

We have been looking for the possibility to build a computer model of costly gas utilization in the course of heat treatment of canned meat. This was necessary for us, as the first part of our long-term research, to be able to accomplish minimized costs by synchronizing heat treatment processes running side by side and by production programming to define completion time of the cans. First, because of our multiple data (paper based, text file, image file, Excel file), we have arranged them under a common user interface, while defining the best one from the data with different precision appearing in several sources. Based on the accurate data we did correlation and regression analysis to define the data influencing the gas consumption and to see whether our present data was enough to develop a model. Since the furnace has to ensure the steam supply of the heat treatment equipment and the heating of the buildings too, we defined the gas consumption of the furnace which is dependent on the environmental temperature.
Losses of human beings
Authors: Vanderstein Noémi
Published: May 2020

Losses are essential in every human being's life. My goal is to make an attempt to introduce the main aspects of loss. I think that losses occur by two modes: in our cultural surroundings and in our identity. Culture plays an important role in people's lives, culture that we are bom into. However, Otherness is a new field of investigating the individuals and of investigating the world at the same time. What is the end of losing culture? What is the end of losing Otherness? To reach the state of being a Subject is the unconscious desire of human beings' psyches. Every human being reaches a development in his thinking, and he becomes a Subject through his losses because these losses serve as profit at the same time.