bluuebunny/crossref_metadata_2025 huggingface dataset:
Efficacy and safety of derazantinib (DZB) in patients with metastatic urothelial carcinoma (mUC) with activating FGFR1/2/3 genetic aberrations (GA): Results from the phase 1b/2 FIDES-02 study.
Authors: Necchi Andrea , Todenhöfer Tilman , Deville Jean-Laurent , Häckl Manuel , Marszewska Michalina , McKernan Phil , Saulay Mikael , Engelhardt Marc , De Santis Maria
Published: March 2023

501

Background: DZB is an oral small-molecule FGFR1/2/3 kinase inhibitor, which showed meaningful clinical benefit in cholangiocarcinoma patients (pts) with FGFR2-driven (fusions, mutations or amplifications) tumors (NCT03230318). The current study explored the activity of DZB in patients with mUC and FGFR1-3 GA (NCT04045613). Methods: Eligible pts with advanced mUC and ≥1 prior lines of standard treatment and FGFR1/2/3 mutations/short variants and rearrangements/fusions confirmed by central/local NGS testing received DZB 300 mg QD (N = 32) or 200 mg BID (N = 17). Primary efficacy endpoint was objective response rate (ORR) by central radiology review per RECIST v1.1. Key secondary efficacy endpoints were disease control rate (DCR), progression-free survival (PFS), and overall survival (OS). Adverse events were assessed according to NCI CTCAE v5.0. Results: From 01/2020 to 01/2022, 282 pts were screened and 49 pts were included in the study and received DZB. The median age was 67 years, 30.6% of pts were female, 94% had an ECOG 0/1, 75.5% had ≥2 prior treatment lines, 77.6% had received prior immune-checkpoint inhibitors. At data cutoff (30-Aug-2022), all pts had discontinued treatment. Confirmed ORR was 8.2% (95% CI 2.2, 19.6) based on 4 PRs (all with FGFR3 S249C mutation/ FGFR3 TACC3 fusion) and the DCR was 28.6% (95%CI: 16.6, 43.3). PFS ranged 0.3-8.8 months, and OS ranged 0.3-21.4 months. Median duration of response was 6.9 months, and longest time on treatment was 18 months. Most common all-grade treatment-emergent adverse events were transaminase increased (40.8%), nausea (38.8%), fatigue (32.7%) and decreased appetite (30.6%). Drug-related retinal events (12.2%), nail toxicities (6.1%), stomatitis (4.1%) and palmar-plantar erythrodysesthesia (PPE) (0%) were infrequent. Safety and efficacy results were similar in patients receiving 300 mg QD or 200 mg BID. Conclusions: Derazantinib showed signals of clinical activity in some patients with mUC and FGFR1-3 GA but the observed ORR and PFS did not meet contemporary benchmarks that would support further clinical development of derazantinib as monotherapy in this indication. Derazantinib showed a well-manageable safety profile with low rates of hand-foot syndrome, stomatitis, nail toxicity and retinal side effects. Clinical trial information: NCT04045613 .
Outcomes of patients with brain metastases from renal cell carcinoma treated with first-line therapies: Results from the International Metastatic Renal Cell Carcinoma Database Consortium (IMDC).
Authors: Takemura Kosuke , Lemelin Audreylie , Ernst Matthew Scott , Wells Connor , Basappa Naveen S. , Szabados Bernadett , Powles Thomas , Davis Ian D. , Wood Lori , Kapoor Anil , McKay Rana R. , Lee Jae-Lyun , Meza Luis A , Pal Sumanta Monty , Donskov Frede , Yuasa Takeshi , Beuselinck Benoit , Gebrael Georges , Choueiri Toni K. , Heng Daniel Yick Chin
Published: March 2023

600

Background: The outcomes of patients with brain metastases from renal cell carcinoma (RCC) are not well characterized due to exclusion of these patients from clinical trials. Methods: Using the IMDC, patients with brain metastases from RCC at the initiation of first-line therapy were analyzed. Baseline patient characteristics, brain-directed local therapies, clinician assessment of best overall response as per RECIST 1.1, and overall survival (OS) were compared across first-line therapies, namely immuno-oncology (IO)-based combination therapy (IO/IO or IO/vascular endothelial growth factor (VEGF)) and anti-VEGF monotherapy (sunitinib or pazopanib). Results: The overall cohort of patients with brain metastases included 775 patients, consisting of 78/1298 (6.0%) and 697/8633 (8.1%) in the IO-based and anti-VEGF cohorts, respectively (p = 0.009). Among the baseline patient characteristics, only the proportion of patients receiving whole-brain radiotherapy differed significantly across the IO-based and anti-VEGF cohorts with proportions of 25.0% and 55.7%, respectively (p < 0.001). Best overall response in all disease sites was 3.4% complete response (CR), 25.9% partial response (PR), 39.7% stable disease (SD), and 31% progressive disease (PD) in the IO-based cohort, whereas it was 0.7% CR, 29.6% PR, 36.7% SD, and 33.0% PD in the anti-VEGF cohort (p = 0.223). The following factors were significantly associated with longer OS on multivariable analysis: IMDC favourable-/intermediate-risk (HR 0.49, 95% CI 0.37–0.65; p < 0.001), IO-based combination therapy (HR 0.51, 95% CI 0.29–0.92; p = 0.026), neurosurgery (HR 0.62, 95% CI 0.47–0.83; p = 0.001), and stereotactic radiosurgery (HR 0.64, 95% CI 0.49–0.84; p = 0.001). Conclusions: Patients with brain metastases receiving IO-based combination therapy may have longer OS than those receiving anti-VEGF monotherapy. Brain-directed local therapies including neurosurgery and stereotactic radiosurgery were associated with longer OS. [Table: see text]
Financial toxicity from first-line TKI plus IO therapies for advanced renal cell carcinoma.
Authors: Benjamin David Joseph , Rezazadeh Arash
Published: March 2023

634

Background: Since the approval of sunitinib for the treatment of advanced renal cell carcinoma (RCC), the first-line treatment landscape has drastically altered with combination tyrosine kinase inhibitor (TKI) plus immunotherapy (IO) regimens. Despite improvements in survival, it remains unclear if these therapies are cost prohibitive for patients or hospitals compared to prior standard of care sunitinib. Methods: Approved TKI plus IO therapies were identified using the US FDA Oncology Announcements website and confirmed with NCCN Guidelines (Version 3.2023). Cost per unit was identified using public data (Lexicomp or manufacturer’s website). We calculated total cost of each treatment regimen using the cost per unit for each therapy and the median duration on treatment as reported in each combination therapy's clinical trial publication. Results: Average PFS benefit from combination TKI plus IO therapies was 8.1 months (range 4-14.7) in comparison with sunitinib. Average cost of TKI plus IO therapy was $443,839.32 compared with $199,541.44 for sunitinib therapy. Conclusions: Average increase in cost of TKI plus IO therapy compared to sunitinib was $244,297.88. For every month of PFS benefit with TKI plus IO combination therapy, there was on average $30,160.23 cost added per month. These increased costs may be prohibitive for many patients and hospitals, particularly in low- and middle-income countries (LMICs). [Table: see text]
Patient perceptions of benefits and risks of adjuvant therapy in renal cell carcinoma.
Authors: Battle Dena , Msaouel Pavlos , Pal Sumanta Monty , Vaishampayan Ulka N. , Staehler Michael D.
Published: March 2023

663

Background: Adjuvant treatment with the immune checkpoint inhibitor (CPI) pembrolizumab and the tyrosine kinase inhibitor (TKI) sunitinib are currently standard of care options for patients with high-risk localized renal cell carcinoma (RCC). However, treatment decisions need to be based on anticipated benefit, toxicity risk, and patient goals and values, particularly since multiple trials testing CPIs and TKIs in the adjuvant setting did not meet their primary endpoints. To improve patient selection and communication, we sought to assess how patients perceive the benefits and risks of adjuvant therapy. Methods: The survey was developed by the Kidney Cancer Research Alliance (KCCure), with multidisciplinary representation from urologic surgeons, medical oncologists and patient advocates. The survey was broadcast between 07/2022 and 09/2022 to patients via website, mailing lists and social media platforms. Out of 1,062 participants 639 patients self-identified with localized RCC and 223 patients had stage 3 RCC at initial diagnosis. 113 patients were offered adjuvant therapy by their doctor, 74 patients reported being treated with or having received treatment with adjuvant therapy (18% treated with TKI, 82% with CPI). Results: When asked to assess risk of recurrence, patients with stage 3 disease assessed their average personal risk to be 47%, 10% higher than what they reported their doctor assessed risk to be (37%). When asked to identify the most important factors related to adjuvant decision making, patients ranked risk of dying from cancer (76%) over severity of possible side effects (43%), chance of having side effects (35%), time required for treatment (24%), and cost of treatment (7%). 49% of patients offered adjuvant therapy believe that treatment reduces the risk of recurrent disease by more than 30% and 25% believe it reduces risk by more than 50%. Among patients receiving or having received adjuvant therapy, 46% completed adjuvant therapy, 17% stopped early due to side effects and 14% recurred while on therapy. Side effects were asymptomatic or mild in 38%, moderate without invasive intervention or hospitalization in 48% severe, requiring hospitalization in 8% and life-threatening in 7%. 22% of patients were told that their side effects would be life-long. Conclusions: Patients with high-risk localized disease estimate their recurrence risk to be higher than what their doctors assess their risk to be. When weighing decisions about adjuvant therapy, patients rank risk of dying from cancer over risks related to toxicity. An overestimation of benefits of adjuvant therapy is noted with one quarter of patients believing that adjuvant therapy will reduce their risk of recurrence by 50 percent or more. The findings highlight the importance of effective communication between patients and providers regarding the risks and benefits of adjuvant therapy to promote an informed and shared decision.
Frailty and overall survival in metastatic castration-resistant prostate cancer treated with abiraterone or enzalutamide.
Authors: Deol Ekamjit Singh , Luo Suhong , Sanfilippo Kristen Marie , Eisen Seth A , Schoen Martin W.
Published: March 2023

71

Background: Abiraterone (ABI) and Enzalutamide (ENZ) are both treatment options for metastatic castration-resistant prostate cancer (mCRPC). However, both drugs have differing pharmacodynamics, so patient factors may selectively impact drug efficacy. Age-associated health deficits make older adults variably susceptible to disease under a syndrome termed frailty. The average age of initial prostate cancer diagnosis is age 66, and the average time to mCRPC progression is 11.7 years. Thus, frailty is an important patient factor to consider in mCRPC, and it may play a role in personalizing drug selection. Methods: Patients treated with ABI or ENZ for mCRPC from September 2014 to June 2017 were identified in the VA and followed until April 2020. Frailty was assessed using the VA frailty index, which looks at ICD-10, CPT, and HCPCS codes to assign a standardized frailty score between 0-1. Patients were categorized as frail if their VA-FI scores were > 0.2. The primary outcome was overall survival (OS) between the ABI and ENZ treatment groups. Cox regression models included age, race, body mass index, PSA, and total Charlson Comorbidity Index (CCI). For frail patients, a propensity score-matched cohort was also created by matching age, race, CCI, and total VA-FI between ABI and ENZ treatment groups. Results: Of the 5,822 patients identified, 57% were initially treated with ABI and 43% with ENZ. The ABI group had a lower mean VA-FI score of 0.192 compared to the ENZ group of 0.203 (p=0.004). Frail patients were older: mean 74.9 years vs. 76.1 years for non-frail (p<0.001). Frail patients had shorter survival than non-frail (18.5 vs. 26.6 months, p<0.001). In multivariable models, frailty was associated with increased risk of death (aHR 1.32, 95% CI 1.23-1.42). Among non-frail patients (n=3508, 60.3%), there was no significant difference in OS between ABI and ENZ treatment. Among frail patients (n=2314, 39.7%), patients treated with ENZ had a 3.5 month greater median OS than ABI (20.7 vs. 17.2 months, p = 0.0003 by log-rank). In frail patients, ENZ was associated with reduced risk of death (aHR 0.85, 95% CI 0.78-0.94). In a propensity matched cohort of 2070 patients, the enzalutamide treatment group had a 3.2 months greater median OS in the enzalutamide group than the abiraterone group (24.1 months vs. 20.9 months, p < 0.001). Conclusions: ENZ was associated with improved OS compared to ABI among frail veterans, but not among non-frail veterans. The improved survival remained significant in a propensity score-matched cohort and models including important covariates. Further assessment of the value of frailty in personalizing drug treatment is warranted to improve the care of older adults with advanced prostate cancer.
The Lung Immune Prognostic Index (LIPI) stratifies prognostic groups and correlates with gut microbiota (GM) in patients with advanced renal cell carcinoma (RCC).
Authors: Silva Carolina Alves Costa , Zoppi Silvia , Reni Anna , Piccinno Gianmarco , Lahmar Imran , Cerbone Luigi , Carril-Ajuria Lucía , Colomba Emeline , Flippot Ronan , Sow Cissé , Segata Nicola , Escudier Bernard , Zitvogel Laurence , Albiges Laurence , Derosa Lisa
Published: March 2023

719

Background: The LIPI score has been reported as an independent prognostic factor in RCC patients treated with immune checkpoint inhibitors (ICI) or tyrosine kinase inhibitors (TKI). Here, we aimed to correlate LIPI score and GM composition in patients with RCC. Methods: We prospectively collected fecal samples of all comers RCC patients who started a 1st or beyond line therapy (standard or clinical trial) in the NCT0457446 at Gustave Roussy. Neutrophil to lymphocyte ratio (dNLR) and lactate dehydrogenase (LDH) were obtained from routine blood tests. Shot gun metagenomic sequencing (MGS) data were analyzed by multivariate and pair-wise/fold ratio . Clinical benefit ratio (CBR, complete response + partial response + stable disease, RECIST1.1) and overall survival (OS, from treatment start) were evaluated. Multivariate analysis (MVA) for OS included age, gender, therapy line, IMDC, histology, hypoalbuminemia. Results: From February 2016 to July 2021, 160 patients were screened and 102 were included. Median age was 61 years (22-89), patients were mostly males (75%) and clear cell histology (90%). Patients were treated in 1st (15%), 2nd (53%) and beyond (32%) lines. Treated with ICI monotherapy (65%), followed by TKI or mTOR (20%) and ICI combination (19%). IMDC was 32% good (G), 54% intermediate (I) and 14% poor (P) and LIPI was 69% G, 25% I and 6% P. Median OS was 42.9, 17.7 and 8.3 months in patients with LIPI G, I and P, respectively (p<0.0001) . Among IMDC risk groups, IMDC G + LIPI G had better OS compared to other subgroups (p=0.017), and those with IMDC P + LIPI P had the worse OS. Overall, LIPI G had higher rates of CBR than I+P LIPI (74% vs 50%; p=0.0158). At MVA, LIPI was independently associated with OS (HR 6.25, 2.02-24.34; p=0.0187). Overall, Parabacteroides merdae and Veillonella parvula were enriched in LIPI I+P, while LIPI G harbored Faecalibacterium prausnitzii. In patients treated with ICI monotherapy, LIPI I+P were enriched with Bacteroides spp ( P. merdae, Phocaeicola vulgatus), and LIPI G had an overrepresentation of Ruminococcaceae unclass bacterium. Conclusions: We report the first MGS study correlating LIPI score and GM composition in RCC patients. LIPI score correlates with clinical outcomes (OS and CBR) and helped to better-stratified IMDC risk groups. Patients LIPI G harbor health-related commensals, while I and P groups are associated with harmful ones. LIPI score could represent a clinically relevant score to stratify mRCC patients. Clinical trial information: NCT04567446 .
Alliance A031902 (CASPAR): A randomized phase (ph) 3 trial of enzalutamide with rucaparib/placebo in first-line metastatic castration-resistant prostate cancer (mCRPC).
Authors: Rao Arpit , Heller Glenn , Ryan Charles J. , VanderWeele David James , Lewis Lionel D , Tan Alan , Watt Colleen , Chen Ronald C. , Kohli Manish , Barata Pedro C. , Gartrell Benjamin Adam , Grubb Robert , Dueck Amylou C. , Wen Yujia , Morris Michael J.
Published: March 2023

TPS277

Background: Despite a growing number of treatment options for first-line mCRPC, approximately 40% of patients (pts) have radiographic progression within the first year. Co-inhibition of androgen receptor (AR) and PARP is a promising therapeutic strategy that leverages synthetic lethality induced by impaired double-strand DNA repair. Two phase III studies have shown improvement in radiographic progression-free survival (rPFS) in HRR-mutant pts with abiraterone + PARPi combinations vs abiraterone alone. However, the results in HRR-wild type pts are conflicting, with only one of the studies demonstrating a benefit with the abiraterone + PARPi combination. ENZ + RUCA has shown an acceptable safety profile & no significant drug-drug interactions (S-DDI) in a phase 1b trial. This allows its evaluation in mCRPC. Methods: CASPAR (A031902) is a phase 3 study in which 984 pts will be randomized on a 1:1 basis to ENZ plus RUCA/PBO. HRR gene aberration is not required for enrollment. All pts will undergo next-generation targeted exome sequencing from archival tumor tissue (new biopsy only required if no archival tissue is available). Treatment will be continued until disease progression and crossover is not allowed. Key eligibility criteria are age ≥ 18 years, ECOG PS 0-2, biopsy-proven prostate adenocarcinoma, progressive (PSA or radiographic) disease per Prostate Cancer Working Group 3 guidelines, measurable or non-measurable disease per RECIST 1.1, no prior treatment for mCRPC (prior docetaxel, abiraterone, darolutamide, or apalutamide in non-mCRPC setting is allowed), no significant uncontrolled comorbidity, and no medications with S-DDI with ENZ/RUCA. Hierarchical co-primary endpoints are overall survival (OS) and rPFS. The OS analysis will be undertaken as a primary endpoint if the rPFS endpoint is met. For a one-sided logrank test with a type 1 error rate equal to 0.025, the study has 90% power to detect a hazard ratio (HR) of 0.71 in rPFS (median rPFS of 15 and 21 months in control and combination arms, respectively), and 80% power to detect an HR of 0.80 in OS (median OS of 32 and 40 months, respectively). Key secondary endpoints are rPFS and OS in pts with vs without pathogenic BRCA1, BRCA2, or PALB2 alterations; and differences in adverse events and quality of life (QOL) outcomes between the treatment arms. QOL assessments include Functional Assessment of Cancer Therapy–Prostate (FACT-P), Brief Pain Inventory Short Form (BPI-SF), and EQ-5D-5L. A key correlative endpoint is the sensitivity of ctDNA testing for HRR gene alterations. Enrollment began in July 2021 & the study is available for participation to all US-NCTN sites. Clinical trial information: NCT04455750 .
PRIMARY2: A phase III, multi-centre, randomised controlled trial investigating the additive diagnostic value of [68Ga]Ga-PSMA-11 PET/CT in men with negative/equivocal MRI in the diagnosis of clinically significant prostate cancer.
Authors: Buteau James Patrick , Moon Daniel , Fahey Michael T , Roberts Matthew , Thompson James , Murphy Declan G. , Papa Nathan , Mitchell Catherine , Kasivisvanathan Veeru , Stricker Phillip , O'Brien Jonathan , Counter William , Sharma Gaurav , Agrawal Shikha , Ho Bao , Yeung Theresa , De Abreu Lourenço Richard , Dhillon Haryana M. , Hofman Michael S , Emmett Louise
Published: March 2023

TPS397

Background: Multi-parametric magnetic resonance imaging (MRI) has an established role for the diagnosis of clinically significant prostate cancer (sPCa), with superior diagnostic accuracy compared with transrectal ultrasound guided prostate biopsy alone. PRIMARY demonstrated significant improvement in sensitivity (97% vs 83%) and negative predictive value (91% vs 72%) with the addition of [68Ga]Ga-PSMA-11 PET/CT (PSMA PET/CT) vs MRI alone. Furthermore, 38% of patients with PI-RADS 2 or 3 were true negative on PSMA PET/CT, a population which may potentially benefit from avoiding transperineal prostate biopsy (TPPB). We hypothesize that the addition of PSMA PET/CT is non-inferior to MRI for the detection of sPCa in men with PI-RADS 2-3 disease, while providing the advantages of reducing unnecessary biopsies and limiting to targeted-only TPPB. Methods: This multi-centre, two-arm, randomized controlled, phase III trial will recruit 660 men with high clinical suspicion of sPC. Participants will be randomized in a 1:1 ratio in permuted blocks, stratified by center. In the experimental arm, participants will undergo a pelvic PSMA PET/CT. Local and central reviewers will interpret independently, based on the PRIMARY Score. Participants with a positive result will undergo targeted-TPPB, whereas those with negative PSMA PET/CT will avoid biopsy. In the control arm, all participants undergo template-TPPB. Patients will continue follow-up for subsequent clinical care for up to two years post-randomization. Key eligibility criteria include an MRI result of PI-RADS 2 with at least one red flag [PSA density >0.1, abnormal digital rectal examination (DRE), strong family history, BRCA mutation, PSA >10, PSA doubling time <36 months, PSA velocity >0.75/year], or PI-RADS 3, having never undergone a prostate biopsy, <cT3 on DRE, and PSA ≤20 ng/mL. The co-primary objectives are to estimate the percentage difference in sPCa between the experimental and control arms, and the percentage of participants who avoid TPPB in the experimental arm. The primary endpoints will be analyzed on the intention-to-treat principle. The main secondary objectives are the percentage difference between arms in insignificant prostate cancer, in complications following biopsy, in health-related quality of life, generalized anxiety, cancer worry, as well as the health economics impact. Patient enrolment began in March 2022, with recruitment expected to take 36 months. Clinical trial information: NCT05154162 .
EDEN (Etude Désescalade sEmiNome): Prospective therapeutic de-escalation and miRNA-M371 biomarker evaluation phase II study for stage IIa/IIb < 3 cm seminomas.
Authors: Vinceneux Armelle , Pasquier David , Blanc Ellen , Attignon Valéry , Blanchard Pierre , Flechon Aude
Published: March 2023

TPS434

Background: At diagnosis, 10 to 15% of testicular pure seminomas have a stage II defined by the presence of retroperitoneal lymph node metastases. The optimal choice of treatment modalities are associated with excellent efficacy but also acute and late toxicities. De-escalating treatment for seminoma patients with stage IIb, IIc and III and good prognosis according to IGCCCG (International Germ Cell Cancer Collaborative Group) based on negative FDG-PET (Fluorodeoxyglucose Positron Emission Tomography) after 2 cycles of EP (etoposide, cisplatine) chemotherapy seems feasible and safe according to SEMITEP cohort 2 results (Loriot Y, and al GETUG SEMITEP Trial: Eur Urol. 2022 Aug;82(2):172-179). Serum levels of microRNA (miR)-371a-3p (miRNA-M371) have been significantly associated with clinical stage and response to treatment in testicular germ cell tumors, with sensitivity and specificity higher than those of classic markers. The aim of the study NCT05529251 is to propose a new therapeutic approach for the stages IIa/IIb. Methods: This phase II, multicenter, prospective, randomized, non-comparative, de-escalation study will include patient with primary testicular seminomatous germ cell tumor with stage IIa/IIb < 3 cm in largest diameter seminoma, histologically proved after orchiectomy and good prognosis according to IGCCCG and LDH (Lactate DesHydogenase) < 2.5 x Upper Limit of Normal (ULN). They must have progressive disease and no prior treatment with radiotherapy or chemotherapy. In case of negative week-3 (after 1 EP cycle) PET-scan, patients will be randomized according to 2 arms ARM A: Boost of radiotherapy 20 to 30 Gray (Gy); ARM B Carboplatin AUC7 chemotherapy. In case of positive week-3 PET-scan: 3 courses of EP chemotherapy (ARM C). Primary outcome will include progression-free rate at 36 months. Secondary Outcome Measures will be serum level of miRNA M371, correlation with response to treatments and PET scan results, overall survival (OS), quality of life and tolerance to treatment. Blood samples (miRNA-M371) will be collected at screening, at the time of randomization before second cycle of chemotherapy or radiotherapy, at the end of treatment and at relapse. Enrollment has started in October 2022. A total of 90 patients will be included in the interventional study, leading to approximately 60 patients with negative FDG-PET randomized. Clinical trial information: NCT05529251 .
SPADE: Design of a real-world observational study of avelumab first-line (1L) maintenance in advanced urothelial carcinoma (UC) in the Asia-Pacific (APAC) region.
Authors: Su Po-Jung , Park Se Hoon , Tsai Yu Chieh , Kim Miso , Wu Wen-Jeng , Gao Seasea , Shin Sang Joon
Published: March 2023

TPS577

Background: UC is a common cancer, with >200,000 new cases reported in the APAC region in 2020. In the global phase 3 JAVELIN Bladder 100 trial, avelumab 1L maintenance + best supportive care (BSC) significantly prolonged overall survival (OS) and progression-free survival (PFS) vs BSC alone in patients with advanced UC that had not progressed with 1L platinum-containing chemotherapy (median OS, 23.8 vs 15.0 months [p=0.0036]; median PFS, 5.5 vs 2.1 months [p<0.0001]), leading to regulatory approvals worldwide and incorporation into international treatment guidelines with level 1 evidence. The objectives of the SPADE noninterventional study are to evaluate real-world patient characteristics, treatment patterns, patient-reported outcomes (PROs) and treatment outcomes with avelumab maintenance administered in patients with advanced UC without disease progression after 1L platinum-based chemotherapy in the APAC region. Methods: SPADE is a multicenter, prospective, observational study ongoing in Australia, Hong Kong, India, Japan, Republic of Korea, Singapore, Taiwan, and other countries. Overall, 286 patients with unresectable locally advanced or metastatic (stage IV) measurable UC of any histology that has not progressed with 1L platinum-containing chemotherapy, for whom avelumab 1L maintenance therapy is planned, will be enrolled. All patients will receive avelumab 800 mg intravenously every 2 weeks (or per local marketing authorization) and will be followed up for 12 months or until avelumab is discontinued. The decision to start avelumab treatment should be made in advance by the treating physician and per local clinical practice. Data collected will include patient demographics (ECOG performance status, renal function, history of UC, primary tumor location, location of metastases, and prior therapy), treatment details for 1L platinum-based chemotherapy (regimen, cycles, and response per RECIST), treatment details for avelumab 1L maintenance (interval from end of chemotherapy until initiation, duration of avelumab treatment, and planned subsequent treatment), and treatment outcomes with avelumab 1L maintenance (6- and 12-month OS and health-related quality of life). Data sources will include medical records collected during routine clinical care. Data for baseline treatment patterns will be summarized using descriptive statistics. OS will be analyzed using the Kaplan-Meier method. Health-related quality of life, including changes over time, will be measured using the EQ-5D-5L and National Comprehensive Cancer Network/Functional Assessment of Cancer Therapy Bladder Symptom Index (NCCN/FACT FBISI-18) questionnaires. An interim analysis is planned after ~30% of patients have been enrolled.
Scaling the Detail: Woolfian Proportions
Authors: Spitzer Jennifer
Published: March 2023

Virginia Woolf seems to have agreed with Georg Lukács about the static quality of details in turn-of-the century fiction: she too condemned the pictorialism that transformed human subjects and their environments into “still lives.” Her own details are anything but static: they are always in motion, zooming in and zooming out, demanding close observation while also enlarging the frame to the global impact of war or the marginalization of women. Woolf uses details dynamically to move between material objects and human minds, and also to move across scales, and thus produces a specifically narrative theory of the detail. This is also a political theory: the fact that she places large and small side by side, often in the same sentence, speaks to her commitment to tracing connections between the particular and the abstract, the mundane and the mystical, the internal world of thoughts and feelings and the external world of actions.
Mechanistic studies in Drosophila and chicken give new insights into functions of DVL1 in dominant Robinow syndrome
Authors: Gignac Sarah J. , MacCharles Katja R. , Fu Katherine , Bonaparte Kywana , Akarsu Gamze , Barrett Thalia W. , Verheyen Esther M. , Richman Joy M.
Published: March 2023

The study of rare genetic diseases provides valuable insights into human gene function. The autosomal dominant or autosomal recessive forms of Robinow syndrome are genetically heterogeneous, and the common theme is that all the mutations lie in genes in Wnt signaling pathways. Cases diagnosed with Robinow syndrome do survive to adulthood with distinct skeletal phenotypes, including limb shortening and craniofacial abnormalities. Here, we focus on mutations in dishevelled 1 (DVL1), an intracellular adaptor protein that is required for both canonical (β-catenin-dependent) or non-canonical (requiring small GTPases and JNK) Wnt signaling. We expressed human wild-type DVL1 or DVL1 variants alongside the endogenous genome of chicken and Drosophila. This design is strategically suited to test for functional differences between mutant and wild-type human proteins in relevant developmental contexts. The expression of variant forms of DVL1 produced a major disorganization of cartilage and Drosophila wing morphology compared to expression of wild-type DVL1. Moreover, the variants caused a loss of canonical and gain of non-canonical Wnt signaling in several assays. Our data point to future therapies that might correct the levels of Wnt signaling, thus improving skeletal growth.
Hardy inequalities in non- Euclidean geometries
Authors: Πασχάλης Μιλτιάδης
Published: March 2023

Σκοπός της παρούσας διδακτορικής διατριβής είναι η διερεύνηση της ισχύος και των ιδιοτήτων της γνωστής ανισότητας του Hardy σε πλαίσια που υπερβαίνουν το κλασικό Ευκλείδειο πλαίσιο. Στο Κεφάλαιο 1 δίνουμε υπόβαθρο για τις ανισότητες Hardy, ιδιαίτερα όσον αφορά το μη-Ευκλείδειο πλαίσιο. Στο Κεφάλαιο 2 παρουσιάζουμε μια μέθοδο ολοκλήρωσης πάνω σε ολοκληρωτικές καμπύλες, που δίνει ανισότητες Hardy για ένα διαφορικό τελεστή πρώτης τάξης X σε κάποια πολλαπλότητα M με μορφή όγκου ω. Το Κεφάλαιο 3 ασχολείται με ανισότητες Rellich ανώτερης τάξης που σχετίζονται με γενικούς ελλειπτικούς τελεστές με σταθερούς συντελεστές, διαφορετικούς από τον κλασικό πολυαρμονικό τελεστη. Σε αυτή την περίπτωση, δείχνουμε ότι μια ανισότητα Rellich μπορεί να εκφραστεί μέσω μιας κατάλληλης απόστασης Finsler που εξαρτάται από το σύμβολο του τελεστή. Αυτή η νέα μορφή ανισότητας αποδεικνύεται να είναι βέλτιση στην περίπτωση που το χωρίο είναι ημιχώρος και το συμβολο ικανοποιεί μια συνθήκη κυρτότητας. Γίνεται επιπλέον σύγκριση για κυρτα χωρία με άλλες πιο κλασικές μεθόδους, που δίνει καλύτερα αποτελέσματα από τα υπάρχοντα σε ορισμένες συγκεκριμένες περιπτώσεις. Εν τέλει, στο Κεφάλαιο 4, ασχολούμαστε με την ευστάθεια της σταθεράς Hardy ως προς διαταραχές του χωρίου στην περίπτωση που η απόσταση μετράται από τμήμα (υποπολλαπλότητα) του συνόρου.Συγκεκριμένα βρίσκουμε ότι η σταθερά Hardy είναι και συνεχής και παραγωγίσιμη (κατά Gateaux) ως προς τέτοιες διαταραχές, υπό την προϋπόθεση ότι το σύνορο ικανοποιεί κάποιες συνθήκες oμαλότητας.
Predictors of face mask use during the COVID-19 pandemic in Indonesia: Application of the health belief model, psychological distress and health motivation
Authors: Wulandari Devi , Purba Fredrick Dermawan , Alfikalia Alfikalia , Kertamuda Fatchiah Ekowati , Rahmania Tia , Sabrina Olivia Ayu , Hidayah Kurnia Nurul , Fatimah Syarifah
Published: March 2023

Background: High infection rates of COVID-19 in Indonesia require attention, especially transmission and prevention behaviors. One way to lower infection rates is the use of face masks. However, people's adherence to its usage when in public is still low. This necessitates the exploration of predictors of the use of masks to increase community compliance. This study further aims to investigate the predictors of face mask use by applying the Health Belief Model, anxiety, stress, depression, and health motivation.

Methods: A total of 255 respondents from Jakarta, Bandung, Tangerang, and Banten filled out an online questionnaire. Furthermore, hierarchical multiple regression was used to detect predictors associated with face mask use.

Results: The results showed that the high perceived benefits and health motivation were higher in individuals who used a face mask when in public, while those who have high perceived barriers likely do not use masks. The respondent's level of psychological distress, including depression, anxiety, and stress were not associated with face mask use.

Conclusions: Therefore, these findings highlight the importance of personal appraisal regarding COVID-19 and its prevention behaviors. Comfortable mask design, and emphasizing the benefits of using masks in the community improve compliance.
Case Report: Tracheal rupture of the newborn: case report and literature review
Authors: Perde FIlip , Voda Theodora , Bosa Maria , Curca Cristian George
Published: March 2023

Tracheal rupture in the newborn represents a rare but severe injury with a difficult therapeutic management and causality interpretation. Here we present the case of a macrosomic female newborn who presented after a dystocic delivery with a series of complications: respiratory impairment, subcutaneous emphysema, pneumothorax, anemia, and finally a diagnosed tracheal tear, which led to a short survival despite the continuous emergency care. The same issues encountered here were also found in the literature and are represented by the delayed diagnosis, the nonspecific initial clinical signs, the lack of a commonly accepted appropriate treatment, the assessment of the mechanism of rupture, the anatomical characteristics of the injury, and the patient management within the whole clinical context.
Evaluation of serum VEGF-A and interleukin 6 as predictors of angiogenesis during peri-implantation period assessed by Transvaginal Doppler Ultrasonography amongst women of prior reproductive failure: a cross-sectional analytical study.
Authors: Pratapan Nair Priya , Shrivastava Deepti
Published: March 2023

Background: Infertility is a wide spectrum of disorder affecting many couples and is defined as the inability of a couple to achieve pregnancy. A series of investigations are required to know the reason behind infertility, yet a small percentage (08-37%) of couples exist, in which no obvious cause is delineated. Different hormones, growth factors and interleukins are responsible for successful ovulation, implantation and further growth of embryo. Endometrial receptivity is an important predictor of the outcome of implantation and further growth of embryo.

Methods: The study would be conducted in a tertiary care centre over a period of two years from July 2022 till July 2024 on non-pregnant unexplained infertile women (63) who will undergo In vitro Fertilisation and Embryo Transfer (IVF-ET) in the following cycle and the result will be compared with the fertile women (21) with same demographic features. The levels of serum Vascular Endothelial Growth factor–A, interleukin-6 will be measured on day 21 of the menstrual cycle in both the group, simultaneously, transvaginal ultrasonography and doppler findings will be measured in both groups to see for endometrial receptivity. The values will be compared for any significance. A new Scoring system will be generated of these three parameters PREDICGIO scoring system after pilot study on ten patients. The values of Serum VEGF-A, IL6 and Doppler findings will be compared between fertile and infertile group to see for significant difference.

Conclusion: The current study helps in determining the suboptimal vasculogenesis and angiogenesis in women with failure in reproduction. It will also help to a great extent in managing patients of reproductive failure with immunomodulator drugs thus providing external angiogenic factors to help in conceiving and carrying pregnancy till term.
The identification of high-performing antibodies for TDP-43 for use in Western Blot, immunoprecipitation and immunofluorescence
Authors: Worrall Donovan , Ayoubi Riham , Fotouhi Maryam , Southern Kathleen , McPherson Peter S. , Laflamme Carl ,   NeuroSGC/YCharOS/EDDU collaborative group,   ABIF Consortium
Published: March 2023

TAR DNA-binding protein 43 (TDP-43) is a DNA/RNA binding protein playing a critical role in the regulation of transcription, splicing and RNA stability. Mutations in TARDBP leading to aggregation, are suspected to be a characteristic feature of various neurogenerative diseases. The lack of well-characterized anti- TDP-43 antibodies acts as a barrier to establish reproducible TDP-43 research. In this study, we characterized eighteen TDP-43 commercial antibodies for Western blot, immunoprecipitation, and immunofluorescence using a standardized experimental protocol based on comparing read-outs in knockout cell lines and isogenic parental controls. We identified many well-performing antibodies and encourage readers to use this report as a guide to select the most appropriate antibody for their specific needs.
Using general-purpose integer programming software to generate bounded solutions for the multiple knapsack problem: a guide for or practitioners
Authors: Shively-Ertas Emre , Lu Yun , Song Myung , Vasko Francis
Published: March 2023

An NP-Hard combinatorial optimization problem that has significant industrial applications is the Multiple Knapsack Problem. If approximate solution approaches are used to solve the Multiple Knapsack Problem there are no guarantees on solution quality and exact solution approaches can be intricate and challenging to implement.  This article demonstrates the iterative use of general-purpose integer programming software (Gurobi) to generate solutions for test problems that are available in the literature. Using the software package Gurobi on a standard PC, we generate in a relatively straightforward manner solutions to these problems in an average of less than a minute that are guaranteed to be within 0.16% of the optimum.  This algorithm, called the Simple Sequential Increasing Tolerance (SSIT) algorithm, iteratively increases tolerances in Gurobi to generate a solution that is guaranteed to be close to the optimum in a short time. This solution strategy generates bounded solutions in a timely manner without requiring the coding of a problem-specific algorithm. This approach is attractive to management for solving industrial problems because it is both cost and time effective and guarantees the quality of the generated solutions.  Finally, comparing SSIT results for 480 large multiple knapsack problem instances to results using published multiple knapsack problem algorithms demonstrates that SSIT outperforms these specialized algorithms.
MEMÓRIAS, DEBATES E PRODUÇÕES: TECENDO ALGUNS DEBATES ACERCA DAS AÇÕES AFIRMATIVAS NO ENSINO SUPERIOR
Authors: MARCELINO SANDRA REGINA DE SOUZA
Published: March 2023

O presente artigo tem como objetivo fazer um breve resgate da implementação da política de cotas na sociedade brasileira e a luta do movimento negro pela democratização e acesso de negros no ensino superior. Dividido em três momentos, no primeiro dialogamos com o passado e o presente da política de cotas; em seguida, resgatamos a experiência pioneira da UERJ e da PUC- Rio narrada em pesquisas, e por fim, apresentamos algumas produções acadêmicas do Centro de Educação e Humanidades e do Centro de Ciências Sociais do Banco Digital de Teses e Dissertações (BDTD/UERJ) datadas entre 2012-2022. As cotas no discurso brasileiro tornaram-se a principal expressão das políticas de ação afirmativa permeada do discurso falacioso do mito da democracia racial e do princípio do mérito. Desde modo, concluímos que a chegada cada vez mais crescente dos “improváveis” nas universidades desestabilizou a ordem, problematizou as equações desiguais instituídas nas relações de poder, contribuiu com as experiências curriculares plurais trazendo para dentro e fora das salas de aula a recomposição epistêmica e os debates acerca da racialização das relações e lugares de poder.
AÇÕES AFIRMATIVAS E EDUCAÇÃO BÁSICA: uma relação em construção
Authors: Pio Alessandra
Published: March 2023

Este trabalho utiliza alguns dos resultados obtidos em pesquisa doutoral, concluída em 2020, para ratificar a necessidade de fortalecermos o debate sobre a Lei nº 10639/2003 como constructo de ação afirmativa para estudantes negras/os da Educação Básica. A pesquisa mencionada constatou, dentre outras questões, que aquilo que consideramos como abertura democrática de espaços escolares elitizados e de prestígio, como as Instituições Federais de Ensino, ainda não é o bastante para atender às demandas da população negra. Observou-se a ausência de ações afirmativas de auxílio financeiro, mas também voltadas para a adequação de currículos e posturas – como demanda a referida lei – possibilitando a permanência de estudantes negras/os com qualidade em instituições de ensino básico.
Development of machine-learning algorithms for 90-day and one-year mortality prediction in the elderly with femoral neck fractures based on the HEALTH and FAITH trials
Authors: Dijkstra Hidde , Oosterhoff Jacobien H. F. , van de Kuit Anouk , IJpma Frank F. A. , Schwab Joseph H. , Poolman Rudolf W. , Sprague Sheila , Bzovsky Sofia , Bhandari Mohit , Swiontkowski Marc , Schemitsch Emil H. , Doornberg Job N. , Hendrickx Laurent A. M.
Published: March 2023

Aims

To develop prediction models using machine-learning (ML) algorithms for 90-day and one-year mortality prediction in femoral neck fracture (FNF) patients aged 50 years or older based on the Hip fracture Evaluation with Alternatives of Total Hip arthroplasty versus Hemiarthroplasty (HEALTH) and Fixation using Alternative Implants for the Treatment of Hip fractures (FAITH) trials.

Methods

This study included 2,388 patients from the HEALTH and FAITH trials, with 90-day and one-year mortality proportions of 3.0% (71/2,388) and 6.4% (153/2,388), respectively. The mean age was 75.9 years (SD 10.8) and 65.9% of patients (1,574/2,388) were female. The algorithms included patient and injury characteristics. Six algorithms were developed, internally validated and evaluated across discrimination (c-statistic; discriminative ability between those with risk of mortality and those without), calibration (observed outcome compared to the predicted probability), and the Brier score (composite of discrimination and calibration).

Results

The developed algorithms distinguished between patients at high and low risk for 90-day and one-year mortality. The penalized logistic regression algorithm had the best performance metrics for both 90-day (c-statistic 0.80, calibration slope 0.95, calibration intercept -0.06, and Brier score 0.039) and one-year (c-statistic 0.76, calibration slope 0.86, calibration intercept -0.20, and Brier score 0.074) mortality prediction in the hold-out set.

Conclusion

Using high-quality data, the ML-based prediction models accurately predicted 90-day and one-year mortality in patients aged 50 years or older with a FNF. The final models must be externally validated to assess generalizability to other populations, and prospectively evaluated in the process of shared decision-making.

Cite this article: Bone Jt Open 2023;4(3):168–181.
Structures of apo Cas12a and its complex with crRNA and DNA reveal the dynamics of ternary complex formation and target DNA cleavage
Authors: Jianwei Li , Jobichen Chacko , Machida Satoru , Meng Sun , Read Randy J. , Hongying Chen , Jian Shi , Yuan Yuren Adam , Sivaraman J.
Published: March 2023

Cas12a is a programmable nuclease for adaptive immunity against invading nucleic acids in CRISPR–Cas systems. Here, we report the crystal structures of apo Cas12a from Lachnospiraceae bacterium MA2020 (Lb2) and the Lb2Cas12a+crRNA complex, as well as the cryo-EM structure and functional studies of the Lb2Cas12a+crRNA+DNA complex. We demonstrate that apo Lb2Cas12a assumes a unique, elongated conformation, whereas the Lb2Cas12a+crRNA binary complex exhibits a compact conformation that subsequently rearranges to a semi-open conformation in the Lb2Cas12a+crRNA+DNA ternary complex. Notably, in solution, apo Lb2Cas12a is dynamic and can exist in both elongated and compact forms. Residues from Met493 to Leu523 of the WED domain undergo major conformational changes to facilitate the required structural rearrangements. The REC lobe of Lb2Cas12a rotates 103° concomitant with rearrangement of the hinge region close to the WED and RuvC II domains to position the RNA–DNA duplex near the catalytic site. Our findings provide insight into crRNA recognition and the mechanism of target DNA cleavage.
Individuals with problem gambling and obsessive-compulsive disorder learn through distinct reinforcement mechanisms
Authors: Suzuki Shinsuke , Zhang Xiaoliu , Dezfouli Amir , Braganza Leah , Fulcher Ben D. , Parkes Linden , Fontenelle Leonardo F. , Harrison Ben J. , Murawski Carsten , Yücel Murat , Suo Chao
Published: March 2023

Obsessive-compulsive disorder (OCD) and pathological gambling (PG) are accompanied by deficits in behavioural flexibility. In reinforcement learning, this inflexibility can reflect asymmetric learning from outcomes above and below expectations. In alternative frameworks, it reflects perseveration independent of learning. Here, we examine evidence for asymmetric reward-learning in OCD and PG by leveraging model-based functional magnetic resonance imaging (fMRI). Compared with healthy controls (HC), OCD patients exhibited a lower learning rate for worse-than-expected outcomes, which was associated with the attenuated encoding of negative reward prediction errors in the dorsomedial prefrontal cortex and the dorsal striatum. PG patients showed higher and lower learning rates for better- and worse-than-expected outcomes, respectively, accompanied by higher encoding of positive reward prediction errors in the anterior insula than HC. Perseveration did not differ considerably between the patient groups and HC. These findings elucidate the neural computations of reward-learning that are altered in OCD and PG, providing a potential account of behavioural inflexibility in those mental disorders.