bluuebunny/crossref_metadata_2025_split huggingface dataset:
NEXT: A single-arm, phase 2, open-label study of adjuvant nivolumab after completion of chemo-radiation therapy in patients with localized muscle-invasive bladder cancer.
Authors: Gupta Sumati , Grass G. Daniel , Maughan Benjamin L. , Jain Rohit K. , Dechet Christopher B. , Sanchez Alejandro , O Neil Brock , Poch Michael Adam , Li Roger , Lloyd Shane , Tward Jonathan David , Phunrab Tenzin Kunsang , Hawks Josiah , Swami Umang , Boucher Kenneth M , Agarwal Neeraj 
Published: February 2022

506 Background: Nivolumab has known efficacy as adjuvant therapy after radical cystectomy in localized muscle invasive bladder cancer (MIBC). We are evaluating the efficacy of nivolumab adjuvant to definitive chemo-radiation therapy (CRT) in MIBC. Methods: In the NEXT study, we are currently enrolling patients with localized MIBC undergoing standard CRT. Participants are started on nivolumab 480 mg IV every 4 weeks (up to 12 doses) within 90 days of completion of CRT. Cystoscopic and scan-based assessments are done every 3 months for the first two years (yrs). The primary endpoint is failure-free survival (FFS) at 2 yrs from the start of CRT, with failure defined as local or systemic disease recurrence. Secondary endpoints include toxicity and quality of life (QOL) assessments. We have planned correlative studies on peripheral blood and tumor tissue. We performed a protocol-defined interim safety and efficacy analysis to assess the 6-month FFS rate with CRT and adjuvant nivolumab. Results: From 8/03/2017 to 9/28/2021, 20 patients were enrolled at two centers; median age is 76 yrs, clinical stage range is T2-T4b, N0-N+, M0; the median number of nivolumab cycles is 6.5, and the median follow-up is 8.9 months. The estimated 6-month FFS rate is 88.2% (95% CI 74.2% - 100%). Disease has progressed in 9 patients, of which 4 have local bladder recurrence (T1 in 3/4) and 5 have distant metastases. The estimated median FFS is 17.1 months (95% CI 8.71 months - infinity). Grade ≥3 treatment-related adverse events (AEs) are noted in 3/20 patients (15%): elevated transaminases, diarrhea, and polymyalgia rheumatica. Grade 3 radiation therapy oncology group (RTOG) AEs occurred in 2 patients. QOL measures are serially evaluable in 13 patients for the first 3 months of adjuvant nivolumab, and are stable in the domains of disease-related physical symptoms, treatment side effects, and function/well-being, while are significantly improved (p=0.023) in the domain of disease-related emotional symptoms. Conclusions: In this first report of the role of immunotherapy adjuvant to CRT for localized bladder cancer, adjuvant nivolumab is well tolerated and has promising efficacy. Clinical trial information: NCT03171025.
Impact of different HER2 expression levels on the outcomes of second-line immunotherapy for metastatic urothelial carcinoma.
Authors: Li Siming , Wu Xiaowen , Yan Xieqiao , Zhou Li , Xu Huayan , Li Juan , Liu Yiqiang , Tang Bixia , Chi Zhihong , Si Lu , Cui Chuanliang , Guo Jun , Sheng Xinan 
Published: February 2022

524 Background: Immunotherapy has become an option of second-line treatment for metastatic urothelial carcinoma (mUC) after the failure of platinum-containing chemotherapy. HER2 expression is an adverse prognostic factor of urothelial carcinoma (UC) while the predictive value of HER2 expression in UC treatment remains unknown. This study attempts to explore the impact of different HER2 expression and gene amplification levels on the outcomes of second-line immunotherapy in metastatic UC. Methods: The baseline clinical data and the outcomes after second-line anti-PD-1 immunotherapy from 2017 to 2021 in 79 patients with metastatic UC who failed to the first-line platinum-containing chemotherapy were reviewed. The expression level of HER2 was detected by immunohistochemistry (IHC) staining ( Anti-Her2/neu, Cat.4B5, Ventana ) from formalin-fixed paraffin-embedded (FFPE) tumor tissue of patients. The copy number amplification level of HER2 gene was detected by second-generation sequencing (NGS) from FFPE tumor tissue of patients. The correlation between HER2 expression and objective response rate (ORR), median progression-free survival (PFS) and overall survival (OS) were analyzed. Results: HER2 expression levels by IHC were performed in 77 patients and the copy number (CN) amplification level of 20 patients with HER2 IHC 2+ were detected by NGS. The median PFS of HER2 negative (IHC 0), low expression (IHC 2 +/ CN - and IHC 1 +) and overexpression (IHC 3 + and IHC 2 +/ CN +) patients were 11.0 months (95% confidence interval [CI]: 1.4-20.6 months), 3.7 months (95% CI: 1.3-6.1 months) and 1.8 months (95% CI: 0.8-2.8 months), respectively, with significant difference in the overall comparison ( P = 0.001) and in the each two comparisons. ORR had a trend to decrease gradually with the increase of HER2 expression level from negative to overexpression (42.4% vs. 31.6% vs. 0%, P = 0.08). However, no correlation between HER2 expression and OS after anti-PD-1 immunotherapy was observed. Conclusions: Different HER2 expression levels have a significant impact on the PFS of the second-line anti-PD-1 immunotherapy in patients with metastatic urothelial carcinoma. The overexpression of HER2 (IHC 3 + and IHC 2 +/ CN +) may be an adverse factor, while the HER2-negative status may be a favorable factor. HER2 expression have potential value in predicting the efficacy of second-line immunotherapy for advanced urothelial carcinoma, which needs further research.
Longitudinal personalized urinary tumor DNA analysis in muscle-invasive bladder cancer from the neoadjuvant immunotherapy trial RJBLC-I2N003.
Authors: Zhang Ruiyun , Zang Jingyu , Xie Feng , Zhang Yue , Shahatiaili Akezhouli , Wang Yiqiu , Du Pan , Jia Shidong , Zhuang Guanglei , Huang Yiran , Chen Haige 
Published: February 2022

552 Background: RJBLC-I2N003 is an investigator-initiated study to evaluate the clinical activity and predictive biomarkers for neoadjuvant immunotherapy with toripalimab (anti-PD-1) in muscle invasive bladder cancer (MIBC). Methods: Twenty patients with pathologically confirmed MIBC were enrolled and received toripalimab (3 mg/kg Q2W, 4 cycles) before radical cystectomy. The safety and efficacy of neoadjuvant toripalimab were assessed. Serial urinary cell-free DNA (ucfDNA) and blood cell-free DNA (bcfDNA) were obtained at baseline and after each cycle of toripalimab treatment. Personalized minimal residual disease (MRD) assays and low-pass whole genome sequencing (LP-WGS) were applied to analyze liquid biopsy samples. Results: Eighteen patients (90%) completed all 4 cycles of neoadjuvant treatment. Grade 3-4 immune-related adverse events occurred in two patients (10%). Eight patients (40%) achieved a pathological complete response (pCR). Thirteen patients (65%) had no remaining invasive disease (pCR or pTisN0/pTaN0). Pre-treatment somatic variants and copy number abnormalities were prevalently detected in ucfDNA as compared to bcfDNA. On-treatment urinary tumor DNA (utDNA) clearance was associated with objective responses. Preliminary concordance was observed between molecular and pathological MRD status. Conclusions: These findings suggest that neoadjuvant administration of PD-1 blockade followed by surgical resection represents a feasible and efficacious approach to treat MIBC. The exploratory biomarker assessment demonstrates the potential utility of longitudinal personalized utDNA analysis to complement existing trial endpoints.
Phase 1 study of JNJ-69086420, an actinium-225-labeled antibody targeting human kallikrein-2, for advanced prostate cancer.
Authors: Morris Michael J. , Sartor A. Oliver , Wong Jeffrey Y.C. , Max Steven I , Xie Hong , Russell Mike , Divgi Chaitanya R , Patricia Daniel , Avadhani Anjali Narayan , Nordquist Luke T. 
Published: February 2022

TPS206 Background: Radioligand therapy for metastatic castration resistant prostate cancer (mCRPC) has been shown to prolong survival, delay disease progression, and improve quality of life, raising hopes that these gains will be amplified with even more cancer-specific targets and more powerful radioligands. Human kallikrein-related peptidase 2 (hK2) is a tumor-associated member of the kallikrein family that shares significant homology to prostate-specific antigen and is minimally expressed in normal non-prostate tissues. JNJ-69086420 (JNJ-420; 225Ac-DOTA-h11B6 [1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid]), is a first-in-class radioimmunotherapy targeted to hK2 antigen. In a phase 0 study of [111In]-DOTA-h11B6, patients (pts) with mCRPC (progressed on standard therapies), treatment with a single dose of [111In]-DOTA-h11B6 (2 mg) with/without 8 mg h11B6, demonstrated safety, good tumor localization, nominal normal-organ uptake, and no difference in PK between 2 and 10 mg antibody mass (Morris et al. J Clin Oncol. 2021 39:6 suppl, 122). We have initiated the first-in-human study to assess the safety, pharmacokinetics (PK), pharmacodynamic (PD), and clinical activity of Ac-225 radiolabeled JNJ-420, to determine its recommended phase 2 dose (RP2D) in adults with advanced PC. Methods: This open-label, multicenter, phase 1 study will recruit approximately 50 men (aged ≥18 years) with advanced PC across dose escalation (Part 1) and expansion (Part 2) parts. Key eligibility criteria: mCRPC with histologic confirmation of adenocarcinoma, Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1, adequate organ function based on hematology and serum chemistry, and 1 or more prior novel androgen receptor-targeted therapies (prior chemotherapy acceptable). Key exclusion criteria: prior treatment with radium/strontium/samarium/radioconjugate therapy, superscan findings as protocol defined, active central nervous system metastases. In Part 1, men will receive intravenous (IV) injection of 50 μCi/ 2 mg JNJ-420 (once every 8 weeks) with one or multiple doses; escalation of dose levels to be based on dose limiting toxicities (DLTs) evaluation, until RP2D identification. In Part 2, JNJ-420 is to be given at one of the RP2D(s) determined in Part 1. Primary endpoint is safety (incidence and severity [grading per NCI-CTCAE V5.0] of AEs including DLTs). Secondary endpoints include prostate specific antigen response rate, overall response rate (PCWG3 modified RECIST 1.1 criteria), PK, PD, immunogenicity, and biomarker analyses. Enrollment began in Dec 2020; as of Sep 2021, 4 sites have been initiated and 14 pts enrolled; currently, dose escalation is ongoing. Clinical trial information: NCT04644770.
ORCHID: A phase II study of olaparib in metastatic renal cell carcinoma patients harboring a BAP1 or other DNA repair gene mutations.
Authors: Ged Yasser , Rifkind Irina , Michalik Amber , Carducci Michael Anthony , Markowski Mark Christopher 
Published: February 2022

TPS400 Background: Metastatic renal cell carcinoma (RCC) comprises a wide set of heterogenous tumors, many of which are increasingly recognized with alterations that affect genomic instability. Several studies demonstrated that DNA repair pathways are frequently disrupted in RCC. Recent In vitro studies have shown that RCC cells are sensitive to PARP inhibitors, with subsequent increased DNA replication stress, DNA synthesis suppression and eventual increased cell cycle arrest. In addition, other studies demonstrated reduced repair of double stranded DNA (dsDNA) breaks following conditional knockout of BAP-1 suggesting that PARP inhibitors may result in synthetic lethality in the setting of BAP-1 inactivation. In light of this we have initiated a phase 2 clinical trial to examine the activity of the PAPR inhibitor olaparib in metastatic RCC with BAP-1 and select DNA repair gene alterations. Methods: This is an open-label, single-arm, investigator-initiated phase II trial of olaparib in patients with metastatic RCC (NCT03786796). Eligibility criteria include age ≥18 years; histologically confirmed, unresectable, locally advanced or mRCC; disease progression after at least one VEGF targeted therapy or immune-checkpoint inhibitor, evidence of deleterious somatic or germline DDR gene alteration ( BAP1, ATM, BRCA1, BRCA2, PALB2, CHEK2, BRIP1, RAD51C, BARD1, CDK12, CHEK1, FANCL, PP2R2A, RAD51B, RAD51D, or RAD54L). A total of 20 patients will be enrolled with the primary endpoint of disease control rate (defined as complete response [CR], partial response [PR], or stable disease [SD]) at six months of treatment) according to RECIST version 1.1. Patients will be treated with olaparib at an initial dose of 150mg by mouth twice daily. If olaparib is tolerated without any grade > 3 adverse events after one month, the dose will be increased to the FDA-approved dose of 300mg by mouth twice daily. Patients will be followed monthly with clinic visits, safety labs, and toxicity assessments. Treatment will be continued until radiographic progression (RECIST version 1.1) or unmanageable toxicity requiring drug cessation. Secondary endpoints include progression-free survival, best overall response, and safety. The study is currently open to enrollment. Clinical trial information: NCT03786796.
Study EV-302: A two-arm, open-label, randomized controlled phase 3 study of enfortumab vedotin in combination with pembrolizumab versus chemotherapy in previously untreated advanced urothelial carcinoma (aUC) (trial in progress).
Authors: Van Der Heijden Michiel Simon , Gupta Shilpa , Galsky Matt D. , Derleth Christina Louise , Lee Sue , Kataria Ritesh S. , Powles Thomas 
Published: February 2022

TPS589 Background: Platinum-based chemotherapy is standard first line (1L) therapy for aUC. Maintenance therapy may be offered for patients (pts) who do not progress on 1L chemotherapy. However, not all pts are eligible for maintenance therapy, with many succumbing to their disease prior to 2L. Therefore, there is a persistent unmet need for safe and effective drug combinations in the 1L setting. Enfortumab vedotin (EV) is a Nectin-4 directed antibody-drug conjugate (ADC) comprised of a fully human mAb conjugated to the microtubule-disrupting agent, monomethyl auristatin E (MMAE), via a protease-cleavable linker. EV has previously shown an OS benefit vs chemotherapy in pts with locally advanced or metastatic urothelial carcinoma who had previously received platinum-based therapy and a PD-(L)1 inhibitor (Powles NEJM 2021). EV is FDA-approved in this and other settings (PADCEV, Seagen Inc., 2021). Preclinical studies showed that MMAE containing ADCs, including EV, induce evidence of immunogenic cell death and can enhance anti-tumor immunity, thereby laying the foundation for EV-PD-1/PD-L1 inhibitor combination (Liu Cancer Res 2020; Cao Can Res 2016). EV-302 will evaluate the efficacy and safety of EV+pembrolizumab (EV+P) combination vs gemcitabine+cisplatin (gem+cis) or carboplatin (carbo) in pts with previously untreated aUC. Methods: EV-302/KN-A39 (NCT04223856) evaluates EV+P combination vs gem+cis or carbo in previously untreated pts with aUC. Eligibility criteria include pts with measurable disease, an ECOG status of ≤2, and eligible to receive EV, P, and cis or carbo. EV+P combination includes EV (1.25 mg/kg) administration on Days 1 and 8 with P (200 mg) on Day 1. Gem+cis or carbo includes: gem (1000 mg/m2) on Days 1 and 8; and cis (70 mg/m2) or carbo (AUC 4.5 or 5) on Day 1 of every 3-wk cycle. Randomization is 1:1 with stratification factors: cis eligibility, PD-L1 expression, and liver metastases. The primary endpoints are PFS and OS for EV+P compared to gem+cis or carbo. Other endpoints include ORR, duration of response, disease control rate, AEs, patient reported outcomes, PK, and biomarkers. The study opened March 2020 with sites actively enrolling globally. Clinical trial information: NCT04223856.
Mortality After Late Breast Cancer Recurrence in Denmark
Authors: Pedersen Rikke Nørgaard , Mellemkjær Lene , Ejlertsen Bent , Nørgaard Mette , Cronin-Fenton Deirdre P. 
Published: February 2022

PURPOSE Late breast cancer (BC) recurrence (ie, ≥ 10 years after primary diagnosis) may have a more favorable prognosis than earlier recurrence. We investigated the risk of BC death after late recurrence, identified prognostic factors, and compared survival after early and late recurrence. METHODS Using the Danish Breast Cancer Group and other nationwide databases, we identified women with early or late BC recurrence during 2004-2018, who were alive 6 months after recurrence. We followed them until BC death, death from other causes, emigration, 10 years, or December 31, 2018, whichever came first. We calculated mortality rates (MRs) per 1,000 person-years (PY) and cumulative BC mortality, for early versus late recurrence, and by characteristics of the primary tumor and the late recurrence. Using Cox regression, we calculated adjusted hazard ratios (HRs) for BC death, accounting for death from other causes as competing risks. RESULTS Among 2,004 patients with late recurrence, 721 died of BC with a median survival time of 10 years (MR = 84.8 per 1,000 PY; 10-year cumulative mortality = 50%). Among 1,528 patients with early recurrence, 1,092 BC deaths occurred with a median survival time of 4 years (MR = 173.9 per 1,000 PY; 10-year cumulative mortality = 72%). We observed a lower hazard of BC-specific death among patients who developed late compared with early recurrence (hazard ratio = 0.72; 95% CI, 0.62 to 0.85). Advanced stage at primary diagnosis, distant metastases, adjuvant treatment for locoregional recurrence, and systemic treatment for distant recurrence were associated with increased mortality after late recurrence. Breast-conserving surgery at primary diagnosis, locoregional recurrence, and surgery for recurrence were associated with lower mortality after late recurrence. CONCLUSION Patients with late recurrence had more favorable prognosis than patients with early recurrence. The localization of recurrent disease was the main prognostic factor for BC death.
Reasoning about location of robot-operated object based on probabilistic ontologies
Authors: Ge Yueguang , Zhang Shaolin , Cai Yinghao , Lu Tao , Wen Dayong , Wang Haitao , Zheng Zekai , Wang Shuo 
Published: February 2022

Background: A robot needs to acquire the location of objects when performing daily tasks. Compared to industrial robots, a service robot faces a more complex and unstructured working environment where the location of the target object is usually uncertain. For example, due to diversity in personal habits and seasons, apples may be located in refrigerators, tables, or other places in the living environment. Methods: We propose a novel method for semantic localization of the robot-operated object based on probabilistic ontologies (PR-OWL) and multi-entity Bayesian networks (MEBN). The probabilistic web ontology language is used to describe and model the highly uncertain knowledge about the storage location of objects in the human household environment. Furthermore, the target location is inferred based on the multi-entity Bayesian network. Results: The proposed method is capable to adapting to environmental changes and achieves reliable probability estimation of object location. Experiments on simulated robotic tasks verify the effectiveness of the method. Conclusions: We show that applying PR-OWL combined with MEBN to locate the target object for the robot is feasible， which can improve the cognitive and self-adaptive ability of the robot.
Cost of Goods Analysis Facilitates an Integrated Approach to Identifying Alternative Synthesis Methodologies for Lower Cost Manufacturing of the COVID-19 Antiviral Molnupiravir
Authors: Peterson Christopher , Paria Sayan , Deshpande Anita , Ahmad Saeed , Harmon Andrew , Dillon John , Laird Trevor 
Published: February 2022

Orally delivered drugs offer significant benefits in the fight against viral infections, and cost-effective production is critical to their impact on pandemic response in low- and middle-income countries. One example, molnupiravir, a COVID-19 therapy developed by Emory, Ridgeback, and Merck & Co., had potential to benefit from significant cost of goods (COGs) reductions for its active pharmaceutical ingredient (API), including starting materials. A holistic approach to identifying, developing, and evaluating optimized synthetic routes, which includes detailed COGs modeling, provides a rapid means to increase the availability, uptake and application of molnupiravir and other antivirals in global markets. Identification and development of alternate processes for the synthesis of molnupiravir has been conducted by the Medicines for All Institute at Virginia Commonwealth University (M4ALL) and the Green and Turner Labs at the University of Manchester. Both groups developed innovative processes based on synthetic route design and biocatalysis aimed at lowering costs and improving global access. The authors then performed COGs modeling to assess cost saving opportunities. This included a focus on manufacturing environments and facilities amenable to global public health and the identification of key parameters using sensitivity analyses. While all of the evaluated routes provide efficiency benefits, the best options yielded 3-6 fold API COGs reductions leading to treatment COGs as low as <$3/regimen. Additionally, key starting materials and cost drivers were quantified to evaluate the robustness of the savings. Finally, COGs models can continue to inform the focus of future development efforts on the most promising routes for additional cost savings. While the full price of a treatment course includes other factors, these alternative API synthetic approaches have significant potential to help facilitate broader access in low- and middle-income countries. As other promising therapeutics are developed, a similar process could enable rapid cost reductions while enhancing global access.
Decision-making in the management of complicated crown fractures in children
Authors: Politi Ioanna , Leith Rona 
Published: February 2022

Complicated crown fractures of permanent teeth following dental trauma in children are a common presentation in the dental practice. The prognosis of these teeth largely depends on the emergency management provided by the dentist. Treatment options include direct pulp capping and partial pulpotomy. While both have been suggested as possible vital pulp therapies for the management of complicated crown fractures, there are no clear recommendations as to when each procedure is indicated to aid the clinician in decision making. This narrative review aims to provide evidence-based recommendations for the optimal management of complicated crown fractures in children. The factors affecting success rates of both direct pulp capping and partial pulpotomy are discussed and a step-by-step guide to carrying out a partial pulpotomy is presented.CPD/Clinical Relevance: This article will assist clinicians in making an evidence-based decision for the optimal management of complicated crown fractures of permanent teeth in children.