bluuebunny/crossref_metadata_2025_split huggingface dataset:
FIGHT-205: Phase II study of first-line pemigatinib (PEMI) plus pembrolizumab (PEMBRO) versus PEMI alone versus standard of care (SOC) for cisplatin (CIS)—Ineligible urothelial carcinoma (UC) with FGFR3 mutation or rearrangement.
Authors: Galsky Matt D. , Powles Thomas , Dreicer Robert , Kitamura Hiroshi , Asatiani Ekatherine , Howe Jason , Zhen Huiling , Oliveira Natalia , Necchi Andrea 
Published: February 2020

TPS592 Background: Fibroblast growth factor receptor (FGFR) 3 gene alterations (GAs) are involved in UC pathogenesis. Pts with metastatic UC and FGFR3 GAs express low programmed cell death ligand 1 (PD-L1) levels; combination with FGFR inhibitors may confer added benefit via tumor-direct and immunomodulatory effects. Preliminary data from a phase 2 monotherapy trial of PEMI (INCB054828), a selective, potent, oral FGFR1–3 inhibitor, confirmed efficacy in previously treated relapsed/refractory pts with UC and FGFR3 GAs (NCT02872714). FIGHT-205, a randomized, open-label, phase 2 study, will assess efficacy and safety of PEMI + PEMBRO vs PEMI alone vs SOC (carboplatin [CARB] + gemcitabine [GEM] or PEMBRO alone) in CIS-ineligible metastatic/unresectable UC with FGFR3 mutation/rearrangement (NCT04003610). Methods: Eligible pts are adults with confirmed metastatic/unresectable UC; ≥1 measurable target lesion (per RECIST v1.1); platinum (PT)/CIS-ineligible; centrally confirmed FGFR3 mutation/rearrangement; ECOG PS ≤2. Exclusions include prior selective FGFR inhibitor, anti-PD-1/PD-L1/2, or co-inhibitory T-cell receptor directed agent; chemotherapy (except adjuvant, neoadjuvant); clinically significant corneal/retinal disorder; Ca/PO4 homeostasis disorder/systemic mineral imbalance with ectopic calcification; untreated CNS metastases. Pts will be randomized (1:1:1) to 3 groups: PEMI 13.5 mg QD (continuous, 21-d cycle) + PEMBRO 200 mg Q3W, PEMI alone (same dose), or SOC (GEM [1000 mg/m2 on D1 + D8] + CARB [AUC 5 (or 4.5) on D1 or D2] Q3W or PEMBRO [same dose] if PD-L1 score high/PT-ineligible). PEMI titration to 18 mg starting at cycle 2 is required for pts without hyperphosphatemia (serum PO4 >5.5 mg/dL) and grade ≥2 treatment-related AEs during cycle 1. Hyperphosphatemia will be managed by diet modifications, PO4 binders, diuretics, or dose adjustments. PEMI will continue until progression/unacceptable toxicity. Primary endpoint is progression-free survival. Secondary endpoints are overall survival, objective response rate, duration of response, safety, and quality of life. Clinical trial information: NCT04003610.
Avelumab as single agent for patients with metastatic or locally advanced urothelial cancer PD-L1+ unfit for cisplatin: The ARIES study.
Authors: Iacovelli Roberto , Buti Sebastiano , Buttigliero Consuelo , De Vivo Rocco , Caserta Claudia , Ferraú Francesco , Galli Luca , Martelli Valentino , Masini Cristina , Mattioli Rodolfo , Merler Sara , Milesi Laura , Naglieri Emanuele , Ricotta Riccardo , Rizzo Mimma , Sacco Cosimo , Santini Daniele , Tambaro Rosa , Verri Elena , Santoni Matteo 
Published: February 2020

TPS596 Background: Urothelial cancer (UC) is the ninth most common cancer worldwide, this tumour has a poor prognosis when in advanced stage. Cisplatin-based chemotherapy is considered the most effective treatment but more than 50% of patients are considered not eligible ( cis-unfit) for this regimen and have a median survival of only 6-9 months. In the past years, the most used chemotherapy regimen for cis-unfit patients was the combination of carboplatin and gemcitabine. Two single arm studies tested the anti-PD-L1/PD1 monoclonal antibodies atezolizumab and pembrolizumab and reported a response rate of 25% with good safety profile in an unselected population for PD-L1 expression. Recently, atezolizumab alone showed longer OS compared to carboplatin-gemcitabine regimen. Avelumab is another fully human anti-PD-L1 IgG1 antibody already tested in urothelial and in other cancers with a promising safety and efficacy profile. Methods: The single arm, phase II ARIES trial (NCT03891238), aims to evaluate the activity and efficacy of avelumab in patients with metastatic or locally advanced UC considered cis-unfit with PD-L1 expression ≥5%. Overall survival is the primary endpoint. Cis-unfit definition includes at least one of the following characteristics (i) ECOG-Performance status=2; (ii) creatinine clearance <60 ml/min; (iii) grade ≥2 peripheral neuropathy or hearing loss; (iv) disease progression within six months after a previous adjuvant/neoadjuvant treatment with cisplatin-based therapy. Avelumab will be administered at standard dose of 10 mg/kg in 1-hour intravenous infusion every 2 weeks (Q2W). Sixty-seven patients will be enrolled, and supportive care is allowed during the study. Avelumab may be continued after radiological progression of disease at physician’s discretion if an improvement of symptoms or not new symptoms will be reported. The study is currently ongoing in twenty centres in Italy. Clinical trial information: NCT03891238.
Efficacy of atezolizumab concurrent with radiotherapy in patients with muscle-invasive bladder cancer (MIBC) (SOGUG-2017-A-IEC(VEJ)-4).
Authors: Vázquez-Estévez Sergio , Fernandez Calvo Ovidio , Alvarez-Fernandez Carlos , Bonfill Teresa , Domenech Montserrat , GarcIa SAnchez JosE , García José Miguel Jurado , Madueño Francisca Martínez , Romero-Laorden Nuria , Sevillano Elena , Núñez Cristina 
Published: February 2020

TPS601 Background: Radical cystectomy (RC) is the standard of care for patients with T2-T4a MIBC. Organ-preserving treatment is an alternative for patients who wish to attempt bladder preservation therapy or are ineligible for cystectomy. This includes maximal transurethral resection of bladder tumour, external beam radiation therapy (EBRT) and concurrent chemotherapy. The 5 and 10 year OS and disease specific survival (DSS) rates in contemporary RC series are comparable to that reported in bladder-preserving series. Due to EBRT can mediate inmunoestimulatory effects and that radiotherapy has been used in combination with different treatment regimens, a considerable interest has been attracted by combinatorial regimens involving EBRT plus checkpoint inhibitors. The purpose of the present study is to explore feasibility and activity of the combination of atezolizumab associated with EBRT after TURBT in the treatment of localized MIBC with preservation intent. Methods: The primary endpoint of this study is to assess the efficacy of atezolizumab concurrent with EBRT in terms of pathological complete response. The secondary endpoints include OS, DSS, disease free survival, bladder intact disease-free survival, number of patients (pts) with muscle invasive and non-muscle invasive local failure, the rate of distance metastases, the rate of pts with bladder preserved, the rate of immediate or late salvage cystectomy and safety profile and tolerability of the combination. Biomarkers will be evaluated as exploratory endpoints. Elegibility criteria include pts with histologically-confirmed diagnosis of MIBC in clinical stages T2-4a N0 M0, who are not candidates for radical cystectomy by medical reasons, refusal or patient’s choice, unfit for cisplatin and PS (ECOG) 0-2. Pts will receive atezolizumab 1.200 mg by IV infusion on Day1 of each cycle every 3 weeks for a total of 6 treatment courses, concurrent with EBRT 60 Gy in 30 fractions over 6 weeks at 2 Gy/day. With 35 evaluable pts and a pCR of 80%, the 95%CI of the estimation would be 0.62–0.92. The study will be stopped if we do not achieve at least 9 pCR among the first 13 evaluable pts. Otherwise, the study will continue until 39 pts. Clinical trial information: 2018-004348-47.
Adding mitomycin to Bacillus Calmette-Guérin as adjuvant intravesical therapy for high-risk, nonmuscle-invasive urothelial bladder cancer (BCGMM; ANZUP 1301).
Authors: Liow Elizabeth Chien Hern , Hayne Dickon , Stockler Martin R. , Martin Andrew James , Sengupta Shomik , Anderson Paul , Ford Kate , Frydenberg Mark , Gorzeman Margot , Green Will , Grummet Jeremy , Hawks Cynthia , Krieger Laurence Eliot Miles , Ischia Joseph , McCombie Steve , Patel Manish , Davis Ian D. ,   The Bladder, Urothelial, and Penile (BUP) Cancer Sub-Committee of the Australian and New Zealand Urogenital and Prostate Cancer Trials Group (ANZUP)
Published: February 2020

TPS602 Background: Adjuvant intravesical bacillus Calmette-Guérin (BCG) decreases disease recurrence and progression in people with high-risk, non-muscle invasive urothelial bladder cancer (NMIBC), however recurrence occurs in 30% despite optimal therapy. Recent meta-analyses evaluating addition of intravesical mitomycin (MM) to BCG showed lower rates of recurrence and cancer-specific mortality in people with NMIBC who received combination regimens. Good quality randomized trials to definitively test this combination are lacking. The BCGMM trial (NCT02948543) will be the largest study to date evaluating this approach in people with high-risk NMIBC. Methods: This open-label phase 3 trial aims to randomize 500 participants, stratified by stage, site of disease, and presence of carcinoma in-situ, to Arm A (BCG induction weekly x6 then monthly x10) or Arm B (BCG + MM weekly x9 then monthly x9). This study is powered to detect a 10% improvement in 2-year disease free survival (DFS) at 5% level of significance with 85% power. Stage 1 of this study, designed to recruit 130 patients to determine rates of treatment completion, activity reflected by cystoscopic findings at 3 months, adverse events, resource use, and health related quality of life, has completed enrolment and successfully established feasibility of this trial protocol. Stage 2, aiming for a further 370 patients, will inform on additional endpoints including differences in DFS, time to recurrence and progression, overall survival, and potential predictive biomarkers, is estimated to complete accrual in December 2020. Successful treatment completion, defined as 75% or more of planned treatment doses, has been achieved in 76% of patients treated in the experimental arm of Stage 1, compared to 60% in those allocated BCG alone. Clinical trial information: NCT02948543.
A multicenter phase II study of avelumab in patients with locally advanced or metastatic penile cancer (PC) who are unfit for, or have progressed on or after platinum-based chemotherapy: (ALPACA).
Authors: Alqaisi Husam , Winquist Eric , Mukherjee Som , Canil Christina M. , Fallah-Rad Nazanin , Sridhar Srikala S. 
Published: February 2020

TPS7 Background: Squamous cell carcinoma of the penis is a rare and highly aggressive malignancy. Combination platinum-based chemotherapy is the standard of care in the metastatic setting. However, it is poorly tolerated and outcomes are dismal, underscoring an urgent unmet need for novel strategies. Since, penile cancers are often HPV-mediated and frequently overexpress PDL1, there is strong rationale to test the PDL1 inhibitor Avelumab, which is a well-tolerated drug in the setting of metastatic PC. Methods: This is a multicenter, single arm, phase 2 study of Avelumab (10mg/kg IV every 2 weeks) in patients with locally advanced or metastatic PC unfit for or progressed on platinum-based chemotherapy. A Simon’s two-stage design will be used where 9 patients will be enrolled in stage 1. If there is at least 1 response defined by iRECIST (complete response [iCR], partial response [iPR], or stable disease [iSD]) the study will proceed to stage 2, where an additional 15 patients will be enrolled. The primary objective is to demonstrate the anti-tumor activity of avelumab by objective response rate (ORR) according to (iRECIST). Secondary endpoints include: PFS, OS in patients determined to have PD-L1 positive tumors (including infiltrating immune cells) by the GMP verified Dako PD-L1 IHC 22C3 pharmDx test with thresholds of <1%, 1-49%, and ≥ 50% to define PD-L1 positivity, and in all enrolled patients. Secondary objectives also include assessing pathologic complete response rate (pCR) for patients undergoing surgery in the treatment time course, evaluation of safety and immunogenicity profile of Avelumab. The study is now open and actively accruing with further centres opening imminently. Funding Source: Pfizer. Clinical trial information: 03391479.
PDIGREE: An adaptive phase III trial of PD-inhibitor nivolumab and ipilimumab (IPI-NIVO) with VEGF TKI cabozantinib (CABO) in metastatic untreated renal cell cancer (Alliance A031704).
Authors: Zhang Tian , Ballman Karla V. , Choudhury Atish Dipankar , Chen Ronald C. , Watt Colleen , Wen Yujia , Zemla Tyler , Emamekhoo Hamid , Vaishampayan Ulka N. , Morris Michael J. , George Daniel J. , Choueiri Toni K. 
Published: February 2020

TPS760 Background: First-line treatment of mRCC has rapidly changed to include IPI-NIVO or CABO, with clinical benefit of each based on the Checkmate 214 and CABOSUN trials. Combination immunotherapy with VEGF therapies have shown benefit in the JAVELIN 101 and KEYNOTE 426 trials over sunitinib. It is yet unclear which patients (pts) benefit most from combination immunotherapy-VEGF inhibitors, and the optimal sequence of drugs. Methods: In an adaptive, randomized, multicenter, phase 3 trial (Alliance A031704, PDIGREE), pts start treatment with induction IPI 1mg/kg and NIVO 3mg/kg intravenously (IV) once every 3 weeks. Key inclusion criteria include clear cell mRCC, IMDC intermediate or poor risk, Karnofsky performance status >70, and no prior treatments for mRCC. Based on 3-month radiographic assessment (after completing IPI-NIVO combination), pts with complete responses (CR) undergo maintenance NIVO 480mg IV every 4 weeks, pts with progression of disease (PD) switch to CABO 60mg oral daily, and pts with non-CR/non-PD are randomized to NIVO 480mg IV every 4 weeks versus NIVO 480mg IV every 4 weeks with CABO 40mg oral daily. Randomization is stratified by IMDC risk criteria and presence of bone metastases. The primary endpoint of the study is overall survival (OS). We hypothesize that 3-year OS rate will improve to 70% for NIVO-CABO compared to 60% for NIVO alone; to achieve 85% power with a two-sided alpha of 0.05 and exponential distribution, 696 patients will be randomized. Accounting for 30% patients with either CR or PD, and 5% dropout from toxicity, up to 1046 pts will be enrolled. Key secondary endpoints include PFS, 12-month CR rate, ORR based on RECIST 1.1 and irRECIST criteria, and toxicity profiles. Quality of life will be assessed based on the FKSI-19, PROMIS-fatigue, and EQ5D-5L questionnaires. Biomarkers associated with CR and association of IL-6 with treatment benefit will be assessed. Other tissue-based and plasma-based biomarkers are planned. Updated enrollment will be presented. Clinical trial information: NCT03793166.
CASSIOPE: A real-world study assessing the use of cabozantinib for the treatment of advanced renal cell carcinoma (aRCC) after vascular endothelial growth factor (VEGF)-targeted therapy in Europe.
Authors: Staehler Michael D. , Hamberg Paul , Bigot Pierre , Suárez Cristina , Barthelemy Philippe , Eymard Jean-Christophe , Laramas Mathieu , Taguieva Pioger Naila , Gross-Goupil Marine , Rink Michael , Masini Cristina , De Vivo Rocco , Gajate Pablo , Azzabi Ashraf , Procopio Giuseppe 
Published: February 2020

TPS770 Background: Cabozantinib, an inhibitor of multiple receptor tyrosine kinases including VEGF receptor 2, and MET and AXL receptors, is approved for the treatment of aRCC in the USA and, in Europe, in treatment-naïve patients with intermediate or poor risk, as well as following VEGF-targeted therapy. The METEOR trial investigated cabozantinib as second-line (2L) or later-line therapy and showed improved progression-free survival (PFS), objective response rate and overall survival vs everolimus. Adverse events (AEs) associated with cabozantinib were generally manageable in METEOR; dose interruptions and reductions occurred in 70% and 60% of patients, respectively. Here we present the design of the CASSIOPE study which aims to assess the real-life use of cabozantinib as 2L or third- or later-line (≥ 3L) therapy for aRCC. Methods: CASSIOPE is an ongoing, European, prospective, non-interventional study in adults with aRCC who have received ≥ 1 prior VEGF-targeted therapy and are initiating cabozantinib as 2L or ≥ 3L therapy according to Summary of Product Characteristics. The primary endpoint is the proportion of patients with dose modifications (interruption, reduction or discontinuation) due to AEs. Secondary endpoints include additional drug utilization parameters, effectiveness (overall best response, PFS), and healthcare resource utilization associated with managing treatment-related AEs. Overall, 680 patients (340 on 2L therapy; 340 on ≥ 3L therapy) will be enrolled to assess the 2-sided 95% confidence interval of the primary endpoint with a precision of ± 5%, assuming a 75% dose modification rate and ≤15% of starting doses lower than 60 mg. Visits will be based on the site's clinical practice, with a maximum follow-up of 12 months after treatment initiation, even if treatment is continued. Data collection started in April 2018. As of 9 October 2019, 336 patients have been enrolled. The overall study duration is expected to be 36 months. An interim analysis is planned when ≥ 340 patients have completed ≥ 3 months follow-up from treatment initiation. The study is funded by Ipsen Pharma. Clinical trial information: NCT03419572; EUPAS19464.
CaboPoint, a phase II, open-label study of cabozantinib as second-line therapy for patients with clear cell metastatic renal cell carcinoma (RCC), whose disease progressed after therapy with checkpoint inhibitors (CPIs).
Authors: Albiges Laurence , Schmidinger Manuela , Taguieva Pioger Naila , Pérol David , Grünwald Viktor 
Published: February 2020

TPS772 Background: Cabozantinib, a tyrosine kinase inhibitor with activity against vascular endothelial growth factor (VEGF) receptors, MET and AXL, is approved for the treatment of advanced RCC (in the USA) in treatment-naïve patients with intermediate or poor risk, as well as following VEGF-targeted therapy (in Europe). Here we present the design of the CaboPoint study evaluating the efficacy and safety of cabozantinib in patients with clear-cell metastatic RCC, whose disease progressed after CPI therapy. Methods: CaboPoint is a phase II, open-label (OL), single-arm study of cabozantinib in adults with unresectable, locally advanced or metastatic RCC with a clear-cell component, whose disease progressed after CPI therapy with ipilimumab and nivolumab alone (cohort A) or in combination with VEGF-targeted therapy (cohort B). The primary endpoint is objective response rate, evaluated by independent review committee. Secondary endpoints include time to response, duration of response, disease control rate, progression-free survival and overall survival. Change in disease-related symptoms and safety/tolerability will also be assessed. During the pre-treatment period, potential participants will attend a screening visit within 15 days of treatment initiation to determine eligibility status. During the treatment period, a target of 250 eligible patients (n = 125 per cohort) at 50 sites across AT, CH, DE, ES, FR, NL and UK will receive OL cabozantinib (60 mg once daily; self-administered at home) for up to 18 months after the last recruited patient has received their first dose. Safety assessments will be conducted every 2 weeks up to week 4, and every 4 weeks thereafter. Patients may continue on cabozantinib after disease progression if clinical benefit is observed. During the post-treatment follow-up period, patients who discontinue early will be contacted at visits every 12 weeks to assess survival status and subsequent anticancer therapy. Each cohort will have an interim analysis when 60% of the patients have reached 12 months of follow-up. The study is funded by Ipsen Pharma. Clinical trial information: NCT03945773.
Mutational spectrum of SMPD1 gene in Pakistani Niemann-Pick disease patients
Authors: Cheema Huma Arshad , Rasool Iqra Ghulam , Anjum Muhammad Nadeem , Zahoor Muhammad Yasir 
Published: February 2020

Objective: Genetic variation analysis of rare autosomal recessive Niemann-Pick disease (NPD) Pakistani patients.
Methods: We sequenced the SMPD1 gene including its all coding and flanking regions in seven unrelated sporadic patients suffering from Niemann-Pick disease through targeted exome sequencing. Genetic variants mapping and their protein predictions were evaluated using different bioinformatics tools and clinical phenotypes were correlated. The study was conducted from January 2018 to March 2019 at The Children’s Hospital Lahore.
Results: We have mapped five different mutations in SMPD1 gene of enrolled patients with a novel homozygous missense variant (c.1718G>C) (p.Trp573Ser) in one patient. A missense mutation (c.1267C>T) (p.His423Tyr) has been identified in three unrelated patients. A nonsense mutation (c.1327C>T) (p.Arg443Term) and one missense mutation (c.1493G>A) (p.Arg498His) mapped in one patient each. A compound heterozygous mutation has been mapped in one patient (c.740G>A) (p.Gly247Asp); (c.1493G>A) (p.Arg498His). Pathogenic effect of novel variant has been predicted through in-silico analysis and has not been reported in general overall population in the globe.
Conclusion: This is the first report of genetic demographic assessment of Niemann-Pick disease in Pakistan. The mapped mutations would be helpful to build a disease variants algorithm of Pakistani population. This will be used for determining disease clinical magnitude along with provision of genetic screening services in affected families.
doi: https://doi.org/10.12669/pjms.36.3.467
How to cite this:Cheema HA, Rasool IG, Anjum MN, Zahoor MY. Mutational spectrum of SMPD1 gene in Pakistani Niemann-Pick disease patients. Pak J Med Sci. 2020;36(3):479-484. doi: https://doi.org/10.12669/pjms.36.3.467
This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
Nuclear distributions, rms radii and form factors with the harmonic oscillator shell model
Authors: Kosmas T. S. , Vergados J. D. 
Published: February 2020

General expressions for calculating nuclear distributions (proton, charge, matter and momentum), mean radii and nuclear form factors are derived by extending recent related works. They are based either on the simple harmonic oscillator shell model or on its modification in which fractional occupation probabilities of the surface orbits are used to fit the experimental elastic electron scattering data. The 40Ca and the values of partial occupation method is applied to the spherical nucleus probabilities are compared with those determined from experimental reaction data.
IndustryConnect: WI-Forschung mit und für die Praxis
Authors: Schubert Petra , Williams Susan P. 
Published: February 2020

ZusammenfassungDer Beitrag beschreibt ein Rahmenwerk für praxisorientierte Langzeitforschung, das an Boyers vier Scholarships angelehnt ist. Das Modell wird im Rahmen der Initiative IndustryConnect seit mehr als fünf Jahren erfolgreich für die gemeinsame Forschung im Themengebiet Digitaler Arbeitsplatz eingesetzt. Die besonderen Erfolgsfaktoren der gemeinsamen Arbeit zwischen Wissenschaft und Praxis werden erläutert, wie zum Beispiel die Schaffung einer gemeinsamen Begriffswelt und das Anlegen einer gemeinsamen Wissensbasis. Das Rahmenwerk umfasst einen ausgewählten Methodenmix, inklusive der speziell entwickelten Methoden eXperience Fallstudien und Milestories, und der damit verbundenen Methodenausbildung für Doktoranden. Typische Ergebnisse aus dieser Art der Forschung sind Erklärungs- und Klassifikationsmodelle, Methoden und Prototypen, für die exemplarische Publikationen aufgeführt werden. Am Ende des Beitrags findet sich ein Bericht über Erfahrungen und Erkenntnisse aus der gemeinsamen Forschungsarbeit „mit und für die Praxis“ sowie eine Ermutigung, dem Aufruf von Nunamaker et al. zu folgen, die „letzte Meile in der WI-Forschung zu gehen“.