bluuebunny/crossref_metadata_2025 huggingface dataset:
Comprehensive metabolomic profiling of plasma from patients (pts) with metastatic urothelial carcinoma (mUC) receiving immune checkpoint inhibitors (ICI) or platinum-based chemotherapy (PBC).
Authors: El Zarif Talal , Adib Elio , Clish Clary , Shukla Sachet A. , Freeman Dory , Thomas Jonathan , Ravi Praful , Tuff Martha , McGregor Bradley Alexander , Mantia Charlene , Ravi Arvind , Sonpavde Guru P.
Published: February 2022

565

Background: Metabolomic profiling of plasma from mUC pts has not been comprehensively examined. Plasma metabolomics may capture the effects of interactions between the malignancy, host and therapy. We hypothesized that Identifying metabolites in plasma from patients with mUC receiving an ICI or PBC may shed valuable insights regarding tumor biology and mechanisms of resistance. Methods: We obtained 0.2 ml plasma before and after starting therapy from pts with mUC receiving an ICI or PBC at the Dana-Farber Cancer Institute. Plasma metabolomic profiling was conducted at the Broad Institute using 3 complementary liquid chromatography tandem mass spectrometry (LC-MS)-based metabolomics platforms. We measured 648 metabolites at baseline prior to starting ICI/PBC and at a second time point in each subject following initiation of ICI/PBC. Metabolite levels were assumed to be normally distributed with log transformation to transform distributions to be approximately symmetric. We performed Wilcoxon-rank sum test to compare the levels of metabolites before and after initiation of the ICI or PBC (significance at p < 0.05). Results: Plasma was available at baseline and during therapy in 53 mUC pts (ICI: n = 43; PBC: n = 10). The median age was 68 (range: 39-86) years and 42 (82.3%) were male. The median time from baseline to the second time point was 4.7 months (range: 0.7-90.2). The ICIs administered were atezolizumab (n = 20), pembrolizumab (n = 16), nivolumab (n = 5), and durvalumab + tremelimumab (n = 1). We identified 20 metabolites that were significantly increased in post-PBC plasma samples (vs. pre-PBC) and 19 metabolites increased in post-ICI (vs. pre-ICI) samples (p < 0.05). All altered metabolites except one (Uracil) were exclusive for each treatment group. The most significant metabolites that increased following initiation of the ICI and PBC are shown in the Table. Evaluation of the association of plasma metabolomics with clinical outcomes and toxicities is ongoing. Conclusions: This is the first report, to our knowledge, of comprehensive metabolomic plasma profiling of pre- and post-ICI and PBC pts with mUC. The metabolomic changes after ICI appear distinct from those seen after PBC. Furthermore, our study sheds insights on potential mechanisms of resistance and new therapeutic targets in pts with mUC.[Table: see text]
Human epidermal growth factor receptor 2 (HER2) and fibroblast growth factor receptor 3 (FGFR3) mutations to reveal biological pathways in urothelial carcinoma.
Authors: Chu Carissa Ellen , De Jesus Escano Manuel , Yip Wesley , Jiang Song , Iyer Gopa , Al-Ahmadie Hikmat A. , Goh Alvin C. , Dalbagni Guido , Bochner Bernard H. , Solit David B. , Pietzak Eugene J.
Published: February 2022

567

Background: Human epidermal growth factor receptor 2 (HER2) (gene name: ERBB2) is a member of the epidermal growth factor receptor (EGFR) family and when mutated, associated with higher grade and stage of localized bladder cancer. Two HER2-targeted antibody-drug conjugates (ADC), trastuzumab emtansine and trastuzumab deruxtecan, are currently approved by the Food and Drug Administration (FDA) for use in gastric/breast cancers with promising application in urothelial carcinoma. Fibroblast growth factor receptor 3 ( FGFR3) is the target of another FDA-approved tyrosine kinase inhibitor erdafitinib and generally associated with more favorable prognosis as well as upper tract carcinoma. The purpose of this study is to characterize ERBB2 and FGFR3 mutations in a prospectively collected cohort of urothelial cancers. Methods: Patients with localized upper or lower tract urothelial carcinoma diagnosed between 2014 and 2020 who underwent a targeted exome sequencing panel of up to 468 cancer genes were identified. If multiple tumors were sequenced, only the diagnostic specimen was included. Analysis of gene alterations, frequency, and associated co-mutations was performed. Descriptive statistics were used to compare baseline patient characteristics. Results: 381 unique ERBB2 or FGFR3 mutated urothelial carcinoma specimens were included in this study. Of note, ERBB2 and FGFR3 mutations were essentially mutually exclusive and included 122 (66%) ERBB2 mutated tumors and 259 (34%) FGFR3 mutated tumors. Patients with tumors harboring FGFR3 mutations were younger (median 70 years IQR 60-76 vs. 74 years IQR 66-78, p<0.05), while patients with ERBB2 mutated tumors were more likely to be male (85% vs 73%, p<0.05). At the time of diagnosis, ERBB2 tumors were more likely to present with advanced (pT2 or higher) disease compared to FGFR3 mutated tumors (48% vs 24%). ERBB2 mutated tumors were more likely associated with RB1, P53, and ARID1A mutations, while FGFR3 mutated tumors were more likely associated with CDKN2A/B and STAG2 mutations (Table). Conclusions: These data highlight divergent biological pathways for patients with targetable mutations in ERBB2 and FGFR3 and are consistent with prior findings in non-muscle invasive bladder cancer. ERBB2 mutated tumors are associated with male gender, more aggressive pathological features and co-mutations with RB1, P53, and ARID1A.[Table: see text]
Recurrence patterns in bladder cancer patients with no residual disease (pT0N0) at radical cystectomy.
Authors: Ladi Seyedian Seyedeh Sanam , Douglawi Antoin , Lee Ryan , Alsyouf Muhannad , Ghoreifi Alireza , Bhanvadia Sumeet , Schuckman Anne K. , Djaladat Hooman , Daneshmand Siamak
Published: February 2022

576

Background: Bladder cancer patients can achieve no residual disease status at the time of radical cystectomy (RC) following transurethral resection (TURBT) alone (pT0) or neoadjuvant chemotherapy (NAC) (ypT0). This population has favorable survival potential, yet limited data is available on their oncological outcomes. We examined the recurrence patterns in these patients and the implications for post-operative surveillance. Methods: A retrospective review of our IRB-approved bladder cancer database identified patients who underwent RC between 2000 - 2019 and were found to have no residual disease (pT0N0). The primary outcome was recurrence-free survival (RFS). Results: A total of 234 patients with a median age of 67 years were included. NAC was used in 89 (38%) patients and 145 (62%) cases were rendered pT0 following TURBT alone. After a median follow up of 44 months, 6/145 (4%) pT0 patients and 10/89 (11.2%) ypT0 cases developed a recurrence. None of the pT0 patients with previous history of clinical Ta/Tis disease had a recurrence after RC. The median time to recurrence was 9 months. All but one of the recurrences in the ypT0 group were within 2 years of cystectomy, while half of the recurrences in the pT0 group occurred after 2 years. Patients with ypT0 had worse 2- and 5-year RFS compared to the pT0 group (85% and 84% vs. 99% and 95%, respectively; p=0.003). Variant histology was noted in 49 (21%) patients and the recurrence rate was higher in this subgroup compared to those with pure urothelial carcinoma (12.2% vs. 5.4%, p = 0.02). Lung metastasis and involvement of distant organs, while rare, was noted at similar rates in both groups (Table). On univariate Cox regression analysis of RFS, clinical T stage > 3 (HR: 6.5, 95%CI: 2.4 – 17.3, p<0.001) and NAC (HR: 4.3, 95%CI: 1.5 – 12.5, p = 0.007) were associated with increased risk of recurrence. Conclusions: Most patients with pT0N0 pathology at the time of cystectomy are cured however metastasis can still develop up to 4 years after surgery. Patients achieving ypT0 after NAC exhibit worse prognosis and shorter times to recurrence, and closer follow-up may be considered.[Table: see text]
Evaluation of tumor genomic variants in Japanese patients with metastatic castration-sensitive prostate cancer (mCSPC) treated with apalutamide: Protocol of a phase 4 study (CUARTET).
Authors: Uemura Hirotsugu , Kamoto Toshiyuki , Uemura Hiroji , Masumori Naoya , Terada Naoki , Akamatsu Shusuke , Koroki Yosuke , Ono Shintaro , Ito Miku , Matsuyama Hideyasu
Published: February 2022

TPS196

Background: Apalutamide is an oral non-steroidal, potent, and highly selective androgen receptor antagonist. Alterations in androgen signaling, DNA repair, and other pathways impact on castration sensitivity and outcomes of androgen antagonists. Currently, there is limited data on the types or effects of variants in prostate cancer (PC)-related genes among Japanese mCSPC (castration-naïve or castration-sensitive) patients treated with apalutamide. Methods: CUARTET is a collaborative phase 4 study with a primary objective of evaluating genomic variants in 73 PC driver genes during apalutamide treatment and hence identify potential biomarkers. Men aged ≥20 years with mCSPC scheduled to start apalutamide at 20 participating institutions will be eligible. Patients previously treated with abiraterone, docetaxel, enzalutamide, apalutamide or darolutamide, are ineligible, as are those who received androgen-deprivation therapy or combined androgen blockade for >6 months before registration or neoadjuvant/adjuvant hormonal therapy for >36 months. The primary endpoint is the changes in genomic variants of 73 PC driver genes between pre- and post-treatment of apalutamide. Secondary endpoints, stratified by baseline genomic variants, include the proportion of patients with nadir prostate–specific antigen (PSA) ≤0.2 ng/mL, PSA–progression-free survival (PFS), PFS, overall survival, time to castration resistance, and PFS2. Other planned outcomes include safety, incidence/severity of apalutamide-related skin rash stratified by single nucleotide polymorphisms or human leukocyte antigen typing, and clinical outcomes in patients with only distant lymph node metastases. The first patient was enrolled in December 2020, and it is expected to enroll 100 patients during the 1.5-year registration period. Eighty-one patients have been enrolled in this study by July 2021. The patients will be followed up for a maximum of 4.5 years. Interim analyses are planned after the last patient has been registered. Results of CUARTET are expected to reveal the genomic variants, including those in androgen signaling-related genes, that are potentially involved in acquired resistance to apalutamide. The results will reveal biomarkers to aid treatment decision making for mCSPC patients, including the treatment options following apalutamide. Clinical trial information: NCT04601441.
PEARLS: A multicenter phase II/III trial of extended field radiotherapy for androgen-sensitive prostate cancer patients with PSMA‐avid pelvic and para-aortic lymph nodes at presentation.
Authors: Murray Julia , Cruickshank Clare , Bird Thomas , Bell Philip , Braun John , Chuter Dave , Davda Reena , Ferreira Miguel Reis , Griffin Clare , Hujairi Nabil , Melcher Alan , Miles Elizabeth , Naismith Olivia , Rekowski Jan , Staffurth John , Syndikus Isabel , Tree Alison , Wilkins Anna , Hall Emma
Published: February 2022

TPS199

Background: Optimal management for lymph node (LN) positive prostate cancer has not yet been determined. With the emerging role of PSMA-PET/CT in diagnostic staging, identification of this disease status is increasing. The superior border for prostate nodal radiotherapy is variable across different centres. PEARLS (CRUK/19/016) aims to show that extending the radiotherapy field to cover the para-aortic LN (up to L1/L2 vertebral interspace) can improve outcomes for prostate cancer patients with PSMA-avid pelvic LN at presentation. The trial is registered: ISRCTN36344989. Methods: PEARLS is a multi‐stage randomised controlled trial. Men with histologically confirmed prostate cancer with PSMA‐avid nodal disease within the pelvis +/‐ para‐aortic region receiving androgen deprivation therapy +/‐ androgen receptor targeted therapy or docetaxel chemotherapy are eligible. Two cohorts defined by extent of LN disease determined by PSMA‐PET/CT will be recruited: cohort A (pelvic LN at or below the L4/L5 vertebral interspace) and cohort B (para-aortic LN below L1/L2 vertebral interspace). Patients are randomly allocated (1:1) to standard field (dependent on cohort) intensity modulated radiotherapy (IMRT) (control) or extended-field IMRT (experimental) in 20 fractions over 4 weeks. In the control group, cohort A will receive 60Gy to the prostate and 44Gy to the pelvis with an integrated boost of 51Gy to PSMA-avid LN and cohort B will receive 60Gy to the prostate only. In the experimental group, participants in both cohorts will receive 60Gy to the prostate and 44Gy to the pelvis and para‐aortic region with an integrated boost of 51Gy to involved LN. In phase II, the primary endpoint is lower gastrointestinal RTOG grade 2+ toxicity at week 18 from start of radiotherapy. Assuming acceptable toxicity in the first 75 participants receiving extended-field IMRT, the study will move to phase III where the primary endpoint is metastasis‐free survival. The trial aims to recruit 714 patients with pelvic LN to detect a hazard ratio of 0.62 in favour of extended-field IMRT and a further 179 patients with para‐aortic LN disease. The trial was launched in the UK on 25 June 2021. Phase II will be conducted in 20 NHS Trusts across the UK. Clinical trial information: ISRCTN36344989.
A randomized, controlled, phase 3 study of darolutamide in addition to androgen deprivation therapy (ADT) versus ADT alone in metastatic hormone-sensitive prostate cancer (ARANOTE).
Authors: KP Haresh , Vjaters Egils , Castellano Daniel , Olmos David , Shore Neal D. , Nevalaita Liina , Testa Isabella , Kappeler Christian , Kuss Iris , Saad Fred
Published: February 2022

TPS200

Background: Previous randomized, phase 3 trials have shown the efficacy of adding docetaxel, abiraterone acetate, enzalutamide, or apalutamide to ADT in improving overall survival and/or radiologic progression-free survival (rPFS) in patients with metastatic hormone-sensitive prostate cancer (mHSPC). However, these combinations are associated with an increased risk of adverse events (eg, fatigue, rash, and cardiovascular events). Darolutamide is a structurally distinct and highly potent androgen receptor inhibitor. In the ARAMIS study, darolutamide has been shown to significantly reduce the risk of death by 31% and have a favorable safety profile in men with nonmetastatic castration-resistant prostate cancer. It has a low incidence of central nervous system−related adverse events, which may be explained by its distinct low blood−brain barrier penetration. Darolutamide has also been shown to have a low potential for drug−drug interactions, allowing flexibility with concomitant medications. ARANOTE will evaluate the efficacy and safety of darolutamide plus ADT in patients with mHSPC (NCT04736199). Methods: ARANOTE is an international, multicenter (ex-US), randomized, double-blind, placebo-controlled, phase 3 study in patients with histologically or cytologically confirmed adenocarcinoma of the prostate and documented metastatic disease by conventional imaging (eg, computed tomography or magnetic resonance imaging) who started ADT ≤12 weeks before randomization. In total, 555 patients will be randomized 2:1 to darolutamide 600 mg twice daily or placebo, plus ADT. Patients will be stratified by the presence of visceral metastases, assessed by central review, and prior local therapy. Patients will be evaluated every 12 weeks for efficacy, safety, and quality of life (using the FACT-P questionnaire) during treatment and active follow-up post treatment. For long-term follow-up, patients will be contacted by telephone every 12 weeks. The primary endpoint is rPFS; secondary endpoints include overall survival, time to castration-resistant prostate cancer, time to prostate-specific antigen progression, and safety. Recruitment is ongoing, and the first patient first visit was on February 23, 2021. The estimated study completion date is September 2025. Clinical trial information: NCT04736199.
A single-arm, open-label, phase 2 study evaluating pacritinib for patients with biochemical recurrence after definitive treatment for prostate cancer: Blast study.
Authors: Kilari Deepak , Szabo Aniko , Hall William A. , Nelson Ariel Ann , Johnson Scott , Giever Thomas A. , Burfeind John , Tolat Parag , Bylow Kathryn A. , Iczkowski Kenneth , Sun Yunguang , Rui Hallgeir , Thomas James P. , Nevalainen Marja
Published: February 2022

TPS220

Background: Androgen deprivation therapy (ADT) achieved with gonadotropin releasing hormone (GnRH) agonist or antagonist is considered the standard of care for men with prostate cancer (PC) who develop biochemical recurrence (BCR) after definitive treatment. ADT is associated with significant adverse effects in this asymptomatic population, and hence there is an unmet need for alternate non-hormonal options. Androgen receptor (AR) and its variants (AR-V) are persistently expressed in the majority of the cells in recurrent PCs and drives PC growth. Jak2-Stat5 signaling has been shown to sustain PC cell viability and is critical for PC tumor growth. Stat5 activation in PC at the time of surgery predicts early PC recurrence. Our investigation of the molecular targets downstream of Jak2-Stat5 signaling have revealed the AR gene as a critical target, and the Jak2-Stat5 pathway represents a target to inhibit expression of diverse AR and AR-V species and thereby control of PC growth. Pacritinib (PAC) is a novel JAK2 inhibitor that suppresses wild-type Jak2 in cell-based assays and has demonstrated promising antitumor activity in myelofibrosis. We hypothesize that PAC inhibition of Jak2-Stat5 signaling will induce biochemical responses in men with recurrent PC by depleting AR and AR-V. Methods: BLAST (NCT04635059) is a single arm, open-label, phase 2 study of PAC (200mg BID) for patients with PC who underwent definitive treatment and developed BCR. Eligibility criteria include histologically confirmed PC, BCR with a PSA doubling time ≤ 9 months, PSA > 0.5 ng/mL, and serum testosterone > 150 ng/dL. 46 subjects will be enrolled with a primary objective to assess the effect of PAC on time to PSA progression. The primary endpoint is six-month PSA progression free survival per PCWG3 criteria. The null hypothesis that the median PSA-progression-free survival is six months will be tested against a one-sided alternative for the six-month PSA-progression-free survival probability exceeding 50%. Secondary endpoints include time to subsequent therapy, safety and toxicity. Exploratory endpoints include effect of PAC on geriatric domains. An interim analysis will be performed when 10 patients have been treated and followed for six months. Accrual began in July 2021. Clinical trial information: NCT04635059.
Talapro-3: A phase 3, double-blind, randomized study of enzalutamide (ENZA) plus talazoparib (TALA) versus placebo plus enza in patients with DDR gene mutated metastatic castration-sensitive prostate cancer (mCSPC).
Authors: Agarwal Neeraj , Azad Arun , Fizazi Karim , Mateo Joaquin , Matsubara Nobuaki , Shore Neal D. , Chakrabarti Jayeta , Chen Hsiang-Chun , Lanzalone Silvana , Niyazov Alexander , Saad Fred ,   For the TALAPRO-3 investigational group
Published: February 2022

TPS221

Background: TALA is a poly(ADP-ribose) polymerase inhibitor (PARPi) approved as monotherapy for germline BRCA1/2-mutated HER 2-negative advanced breast cancer. PARPi have demonstrated substantial clinical efficacy in metastatic castration-resistant prostate cancers (mCRPC) with alterations in DNA damage response (DDR) genes involved directly or indirectly in homologous recombination repair (HRR). Phase 3 study findings (de Bono et al. N Engl J Med. 2020;382:2091-2102) resulted in the approval of olaparib for mCRPC. ENZA is an androgen receptor (AR) inhibitor and established therapy for mCSPC. Since PARP activity has been shown to support AR function, PARP inhibition is expected to increase sensitivity to AR-directed therapies. In addition, AR blockade downregulates HRR gene regulation, which has been hypothesized to induce a “ BRCAness ” phenotype . A phase 2 study of TALA monotherapy (TALAPRO-1) demonstrated robust antitumor activity in men with heavily pretreated, HRR-mutated mCRPC . The Phase 3, double-blind, randomized trial TALAPRO-3 (NCT04821622) herein presented will compare the combination of TALA plus ENZA versus placebo plus ENZA in men with mCSPC with DDR/HRR alterations. Methods: Approximately 550 patients with mCSPC harboring DDR/HRR alterations will be randomized to TALA (0.5 mg once daily) plus ENZA (160 mg once daily) or placebo (once daily) plus ENZA (160 mg once daily). Key eligibility criteria include age ≥18 years; histological diagnosis of prostate cancer; alterations in 12 DDR/HRR genes known to sensitize to PARPi ( ATM, ATR, BRCA1, BRCA2, CDK12, CHEK2, FANCA, MLH1, MRE11A, NBN, PALB2, RAD51C); and metastatic disease (no brain metastases). Primary endpoint is rPFS (time to radiographic progression in soft tissue per RECIST 1.1 or in bone per PCWG3 criteria by investigator, or death). Secondary endpoints include overall survival, safety, and patient-reported outcomes. Patient recruitment is planned at approximately 285 sites in 27 countries, including the US and Europe, South America, South Africa, and Asia-Pacific. Clinical trial information: NCT04821622.
Window-of-opportunity clinical trial platform for evaluation of novel treatment strategies in renal cell cancer (WIRE).
Authors: Sipple Jamal A N , Thomas Martin G , Mossop Helen , Wason James , Gallagher Ferdia , Chhabra Anita , Warren Anne , Stone John , Venugopal Balaji , Oades Grenville , Welsh Sarah Joanne , Stewart Grant D.
Published: February 2022

TPS406

Background: Renal cell cancer (RCC) is the 7th commonest cancer in the UK. The WIRE trial ‘exploits’ a window-of-opportunity between clear cell RCC diagnosis and nephrectomy to use vascular endothelial growth factor tyrosine kinase inhibitors, PARP inhibitors, and immune checkpoint inhibitor therapies in isolation and in combination. WIRE aims to provide biological proof-of-mechanism of these therapies, and build on encouraging pre-clinical evidence of DNA damage response inhibition to be an effective future therapeutic strategy in RCC. Methods: WIRE is a phase II, multi-IMP, multi-arm, non-randomised clinical trial featuring a Bayesian adaptive design with five treatment arms, and three recruitment stages per arm. The treatment groups: cediranib, cediranib and olaparib, olaparib, durvalumab, and durvalumab and olaparib form the initial set of therapy options with the opportunity for additional treatments to be deployed on this platform-trial in future. The primary endpoint for the first three arms is tumour capillary permeability, measured using multiparametric MRI, defined as a 30% reduction in Ktrans compared to pre-treatment. Whereas in the remaining two arms the primary endpoint is changed to intra-tumoural CD8 positive T cells, defined as an increase of 30% cell count compared to pre-treatment. Up to 76 evaluable participants will be recruited. Monotherapy arms will recruit a maximum of 12 participants each, whereas a maximum of 20 participants will be recruited into each dual-therapy arm. Participants are assigned to the current recruiting arm for treatment lasting between 14 and 28 days before proceeding with standard-of-care nephrectomy. Participants will undergo a biopsy and imaging before and after treatment for primary endpoint analysis, alongside blood and urine collections for translational endpoints. A final two follow-up visits are scheduled before concluding the trial pathway. Rapid interim analysis will follow at the end of a recruitment stage to determine whether to cease recruitment to the current treatment arm due to biological response, or due to futility – defined as lacking in promising evidence for proof of mechanism. Alternatively, if more data is required, recruitment will continue within the same treatment arm until the next interim analysis, where endpoints are re-examined. This highly-efficient design accelerates the exploration of multiple therapies with a strong emphasis on determining early proof-of-mechanism. Promising therapies can then be taken forward to later phase trials in RCC with greater confidence. Clinical trial information: NCT03741426.
SunRISe-1: Phase 2b study of TAR-200 plus cetrelimab, TAR-200 alone, or cetrelimab alone in participants with high-risk nonmuscle-invasive bladder cancer unresponsive to Bacillus Calmette-Guérin who are ineligible for or decline radical cystectomy.
Authors: Van Der Heijden Michiel Simon , Cutie Christopher , Hampras Shalaka , Indoria Charu , Stewart Rachel , Acharya Milin , Stromberg Katherine , Li Xiang , Beeharry Neil , Maffeo John , Jacob Joseph M
Published: February 2022

TPS593

Background: Treatment options are limited for patients with high-risk non-muscle-invasive bladder cancer (HR-NMIBC) unresponsive to intravesical bacillus Calmette–Guérin (BCG). TAR-200 is an intravesical drug delivery system for local continuous release of gemcitabine within the bladder. The current study will assess the rate of complete response (CR) upon treatment with TAR-200 + systemic cetrelimab (CET [anti–PD-1 antibody]), TAR-200, and CET in BCG-unresponsive participants with HR-NMIBC who are ineligible for or decline radical cystectomy (RC). Methods: SunRISe-1 (NCT04640623) is an open-label, parallel-group, multicenter phase 2b study designed to assess the efficacy and safety of TAR-200 + CET, TAR-200 alone, and CET alone in participants with BCG-unresponsive HR-NMIBC. Eligible participants are aged ≥ 18 years with ECOG PS 0, 1, or 2 and recurrent or persistent histologically confirmed HR-NMIBC (carcinoma in situ) with or without papillary disease (T1, high-grade Ta), who have been diagnosed within 12 months of last BCG treatment and are ineligible for or declined RC. Participants (N≈200) are randomized 2:1:1 to receive TAR-200 + CET (Cohort 1, n≈100), TAR-200 (Cohort 2, n≈50), or CET (Cohort 3, n≈50). In Cohorts 1 and 2, participants receive intravesical TAR-200 every 3 weeks through Week 24, and every 12 weeks thereafter until Week 96. In Cohorts 1 and 3, participants receive CET until Week 78. Primary disease assessments (cystoscopy, urine cytology, transurethral resection of bladder tumor [TURBT], and magnetic resonance imaging/computed tomography) are made at baseline; subsequent cystoscopy and centrally read urine cytology are performed every 12 weeks through Year 2, every 24 weeks until end of Year 3, and in Year 4 and Year 5 in accordance with institutional standards of care. TURBT is conducted at 24 and 48 weeks. The primary end point for the 3 cohorts is overall CR rate at any time point. Secondary end points include duration of response (ie, from time of first CR achieved to first evidence of recurrence, progression, or death [whichever is earlier] for participants who achieve a CR), overall survival, PK immunogenicity of cetrelimab, safety and tolerability, and patient-reported outcomes. Exploratory end points include incidence and time to cystectomy (measured from randomization to date of cystectomy), biomarkers, and health care resource utilization. This study opened in January 2021 and is enrolling participants at ≈165 study sites worldwide. Currently, the study is active in 13 countries with 12 participants enrolled as of September 12, 2021. Clinical trial information: NCT04640623.
A prospective, single-center, phase II randomized controlled trial to evaluate the safety, feasibility, and preliminary efficacy of exercise during intravesical therapy for nonmuscle invasive bladder cancer.
Authors: Arthuso Fernanda Z. , Fairey Adrian S. , Boulé Normand G. , Courneya Kerry S.
Published: February 2022

TPS600

Background: Non-muscle invasive bladder cancer (NMIBC) accounts for about 75% of newly diagnosed bladder cancers. The treatment for NMIBC initially involves transurethral resection of the bladder tumor followed by six weeks of induction intravesical therapy. NMIBC has a high rate of recurrence (31-78%) and progression (15%). Moreover, bladder cancer and its treatments may affect patient functioning, quality of life, and increase the risk of cardiovascular mortality. Exercise is a safe and effective intervention for many cancer patients groups, however, no studies have examined exercise during intravesical therapy for NMIBC. Bladder cancer and exeRcise trAining during intraVesical thErapy (BRAVE) is the first phase II randomized controlled trial designed to evaluate the safety, feasibility, and preliminary efficacy of exercise for NMIBC patients during intravesical therapy. An exploratory aim is to track the short-term bladder cancer recurrence and progression rates for each trial arm. Methods: BRAVE has a target sample size of 66 men or women diagnosed with NMIBC undergoing intravesical therapy with chemotherapy or immunotherapy agents. Participants are being randomly assigned to usual care or exercise intervention, which consists of three supervised, high-intensity interval training sessions/week for 12-weeks. Safety is being evaluated by any adverse events during the physical fitness assessments or exercise sessions. Feasibility will be evaluated by eligibility, recruitment, adherence, and attrition rates. Preliminary efficacy endpoints are cardiorespiratory fitness assessed by peak oxygen consumption (VO2peak) at 6-week (post-intravesical therapy) and 3-month surveillance cystoscopy; and complete response (CR), defined as negative cytology, imaging, and cystoscopy and, when indicated, a negative biopsy. CR will be assessed at 3-month and one-year surveillance cystoscopy follow-up. Statistical analyses will follow the intention-to-treat approach. Analysis of covariance will compare between-group VO2peak differences at post-intervention (pre-cystoscopy). Study enrolment started May 24, 2021 and is ongoing. As of October 4, 2021, we have screened 17 NMIBC patients scheduled for intravesical therapy for eligibility; 16 (94%) were ineligible for medical (n = 11), language (n = 3), or location (n = 2) reasons. All the medical reasons included severe cardiovascular diseases. One eligible patient declined due to travel distance to the facility. In the face of a slower-than-expected recruitment rate, eligibility was extended to patients in the maintenance phases of treatment for NMIBC, where patients receive three weekly instillations of intravesical therapy. Clinical trial information: NCT04593862.
A phase 2 study of the efficacy and safety of INCMGA00012 in advanced penile squamous cell carcinoma (PSqCC): ORPHEUS.
Authors: Garcia del Muro Xavier , Riva François , Cuellar M. Andres , Maroto-Rey Pablo , Castellano Daniel E. , Giannatempo Patrizia , Climent Duran Miguel Angel A. , Necchi Andrea , Pérez-Valderrama Begoña , Gomez De Liano Lista Alfonso , Garcias-Espana Carmen , Puente Javier , Ros Silverio , Santander Carmen , Masini Cristina , Martínez de Falcon Marta , Garcia Almudena , Sampayo-Cordero Miguel , Malfettone Andrea , Paez David
Published: February 2022

TPS8

Background: PSqCC is a rare tumor with poor prognosis and limited therapeutic options. The current standard of care for advanced disease has been palliative platinum-based chemotherapy, with only marginal survival benefit. Recent data has shown that the majority of PSqCC patients present high levels of programmed death-ligand 1 (PD-L1). The ORPHEUS trial is evaluating the efficacy and safety of INCMGA00012 –a programmed cell death 1 (PD-1) antagonist– in patients with unresectable, locally advanced or metastatic PSqCC. Methods: ORPHEUS is an international, multicenter, open-label, single-arm, phase 2 clinical trial. Eligible patients are male aged ≥18 years with locally advanced or metastatic PSqCC, ECOG performance status of 0-1, adequate organ function, a life expectancy of ≥12 weeks, and with no prior treatment with PD-1 or PD-L1/2 agents. A total of 18 patients will be enrolled to receive INCMGA00012 500 mg administered intravenously on day 1 of each 28-day cycle. Treatment will continue until progressive disease or unacceptable toxicity. Tumor assessments per Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 and immune-related RECIST will be performed approximately every 8 weeks for the first 6 months and every 12 weeks thereafter until progressive disease. The primary endpoint is objective response rate. Secondary objectives include additional efficacy outcomes (clinical benefit rate, progression-free survival (PFS), 6-month PFS, duration of response, time to progression, overall survival, and maximum tumor shrinkage) and safety evaluated as per NCI-CTCAE 5.0. Exploratory objectives will evaluate efficacy based on immune-related RECIST; predictive and prognostic biomarkers; impact of INCMGA00012 on human immunodeficiency virus (HIV) control in patients known to be HIV-positive. The sample size calculation is based on an exact binomial test. At least 4 responders (22.2%) among 18 patients will be adequate to justify further investigation of this strategy. The analyses were designed to attain an 80% power, with a 10% dropout rate assumption, at a nominal one-sided α level of 5%. The response probabilities for null (H0) and alternative hypotheses (H1) were H0: ≤ 5% and H1: ≥ 25%, respectively. All 18 planned patients have been enrolled since the trial began in March 2020. Clinical trial information: NCT04231981.
Identification of Recurrent Insertions and Deletions in Exon 18 and 19 of Human Epidermal Growth Factor Receptor 2 as Potential Drivers in Non–Small-Cell Lung Cancer and Other Cancer Types
Authors: Yin Yan , Song Lijie , Shi Dongsheng , Liu Bin , Li Xiangke , Yang Minjie , Liu Bihao , Wang Dejuan , Qin Jianwen
Published: February 2022

PURPOSE

Human epidermal growth factor receptor 2 (HER2) belongs to the same family as epidermal growth factor receptor (EGFR) and is known as an important cancer driver gene. Insertions and deletions (indels) are frequent driver mutations in both EGFR and HER2. The most common HER2 indels are the exon 20 insertions within the kinase domain, while others are rarely reported. Our study aimed to investigate other indels of HER2 that may act as driver mutations in Chinese patients with different cancer types.

METHODS

In this retrospective study, patient samples were subjected to targeted sequencing covering HER2 and other cancer-related genes. Mutation profiles of patients harboring HER2 exon 18/19 indels were described. Identified HER2 exon 18/19 indels in our study were compared with external data from COSMIC. In silico and in vitro analyses were performed on selected indels of HER2 exon 18 and 19, respectively.

RESULTS

A total of 25 indels in HER2 exon 18/19, 17 of which being recurrent, were identified in 20 of 53,591 patients with lung cancer (0.037%), two of 5,888 patients with colorectal cancer (0.034%), two of 3,774 patients with breast cancer (0.053%), and one of 14 patients with urothelial carcinoma of the renal pelvis (7.1%). Most patients harboring HER2 exon 18/19 indels were absent of known driver mutations. In lung cancer, mutation profiles were comparable between patients carrying HER2 exon 18/19 indels and the two established HER2 drivers (exon 20 insertions and S310 mutations). The in silico and in vitro analyses suggested an activated state conferred by HER2 exon 18/19 indels, which could be targeted by different tyrosine kinase inhibitors.

CONCLUSION

Our study revealed a class of rare but unique indels in HER2 exon 18/19, which may act as driver mutations in several cancer types.
Quasinormal modes of novel 4D Einstein-Gauss-Bonnet Anti-de Sitter black holes
Authors: Ma Hong
Published: February 2022

We comprehensively analyze the Quasinormal Modes (QNMs) of the external matter field perturbation (including scalar, electromagnetic and Dirac field perturbation) and the gravitational perturbation (including odd and even parity perturbation) of novel 4D Einstein-Gauss-Bonnet (EGB) black holes (BHs) in Anti-de Sitter (AdS) spacetime. The corresponding master equation in the form of perturbations and their respective effective potential is derived. Here we focus on the influence of the cosmological constant Λ, coupling parameters α and angular quantum numbers l on the QNMs frequency of novel 4D EGB AdS BHs. The results show that with the increase of the absolute value of the coupling parameters α and angular quantum numbers l, the oscillation of the novel 4D EGB BHs is enhanced, but the decay decreases. However, as the absolute value of the cosmological constant Λ increases, the oscillation and decay of the novel 4D EGB BHs becomes faster and faster. Therefore, the analysis of QNMs by the dynamic evolution image provides direct evidence for the local stability of the novel 4D EGB AdS BHs.
Markov property of Lagrangian turbulence
Authors: Fuchs A. , Obligado M. , Bourgoin M. , Gibert M. , Mininni P. D. , Peinke J.
Published: February 2022

Based on direct numerical simulations with point-like inertial particles, with Stokes numbers St = 0, 0.5, 3, and 6, transported by homogeneous and isotropic turbulent flows, we present in this letter for the first time evidence for the existence of Markov property in Lagrangian turbulence. We show that the Markov property is valid for a finite step size larger than a Stokes-number-dependent Einstein-Markov coherence time scale. This enables the description of multi-scale statistics of Lagrangian particles by Fokker-Planck equations, which can be embedded in an interdisciplinary approach linking the statistical description of turbulence with fluctuation theorems of non-equilibrium stochastic thermodynamics and local flow structures. The formalism allows estimation of the stochastic thermodynamics entropy exchange associated with the particles Lagrangian trajectories. Entropy-consuming trajectories of the particles are related to specific evolution of velocity increments through scales and may be seen as intermittent structures. Statistical features of Lagrangian paths and entropy values are thus fixed by the fluctuation theorems.
Plastic Matter
Authors: Davis Heather
Published: February 2022

Plastic is ubiquitous. It is in the Arctic, in the depths of the Mariana Trench, and in the high mountaintops of the Pyrenees. It is in the air we breathe and the water we drink. Nanoplastics penetrate our cell walls. Plastic is not just any material—it is emblematic of life in the twentieth and twenty-first centuries. In Plastic Matter Heather Davis traces plastic’s relations to geology, media, biology, and race to show how matter itself has come to be understood as pliable, disposable, and consumable. The invention and widespread use of plastic, Davis contends, reveals the dominance of the Western orientation to matter and its assumption that matter exists to be endlessly manipulated and controlled by humans. Plastic’s materiality and pliability reinforces these expectations of what matter should be and do. Davis charts these relations to matter by mapping the queer multispecies relationships between humans and plastic-eating bacteria and analyzing photography that documents the racialized environmental violence of plastic production. In so doing, Davis provokes readers to reexamine their relationships to matter and life in light of plastic’s saturation.
Covid-19: Vacina boa é a aplicada de forma adequada
Authors: Hott Márden Cardoso Miranda
Published: February 2022

Na atualidade, fotografar ou gravar o instante da imunização contra a Covid-19 se tornou rotina compartilhada nas redes sociais. Essa exposição instigou a observação de uma questão relevante: a técnica de aplicação está correta? Com a veiculação de imagens, é possível visualizar as vacinas sendo administradas em diferentes áreas do músculo deltoide, o que pode acarretar efeitos adversos. A otimização da qualificação técnica e pedagógica dos profissionais que elaboram e ministram as capacitações, bem como o envolvimento efetivo dos vacinadores nos treinamentos para injeção intramuscular é uma necessidade constante para evitar mais danos à saúde da população.
Estimated number of deaths directly avoided because of COVID-19 vaccination among older adults in Colombia in 2021: an ecological, longitudinal observational study
Authors: Rojas-Botero Maylen Liseth , Fernández-Niño Julián Alfredo , Arregocés-Castillo Leonardo , Ruiz-Gómez Fernando
Published: February 2022

Background: Colombia’s national COVID-19 vaccination plan began in February of 2021. It gave priority to older adults, who constituted 77.7% of deaths from this illness in the year 2020. The main goal of the plan is to decrease specific mortality and the number of serious COVID-19 cases, however, the number of deaths avoided by this strategy is unknown. The objective of this study was to estimate the number of avoided deaths in Colombia by fully vaccinating older adults against COVID-19, during the first year of the implementation of the national vaccination plan.

Methods: This study took on the design of an ecological, longitudinal study. Full vaccination coverage for older adults was calculated for each epidemiological week and age group from March to December 2021, based on which the number of avoided COVID-19 deaths was estimated. A sensitivity analysis was performed taking into account variations in the vaccines’ effectiveness by age group.

Results: In Colombia, over 5.3 million adults 60 years of age and older received full COVID-19 vaccinations between March and December 2021. During that same period, nearly 46,000 deaths of older adults from this cause were registered. We estimated that vaccination has avoided around 22,000 more older adults from dying from COVID-19 in Colombia, that is, 32.4% of expected deaths in 2021. According to the sensitivity analysis, the number of lives saved ranged from 19,597 to 36,507.

Conclusions: Colombia’s strategy to vaccinate older adults against COVID-19 has avoided mortality for this age group from being 48.0% higher than what was observed during the study period. Even more lives have been saved when taking into account the parameters that were defined and the omission of the contribution from partial vaccinations.
Necrotizing sialometaplasia
Authors: Patel Monica , Cullotty K , Richards A
Published: February 2022

In this case of a 45-year-old woman, who attended the primary care service at Birmingham Dental Hospital with widespread ulceration affecting the hard palate, histopathological, haematological and immunological testing confirmed a diagnosis of necrotizing sialometaplasia (NS), a rare benign minor salivary gland condition. The aetiology of NS is unknown; however, it is thought to represent necrosis of the mucoserous acini due to ischaemia. The clinical features of NS are similar to of squamous cell carcinoma and histopathological investigations may be required to exclude malignancy.

CPD/Clinical Relevance: The article highlights the importance of recognizing necrotizing sialometaplasia to prevent misdiagnosis and ensure correct management is undertaken.
Fast reconstruction of hyperspectral images from coded acquisitions using a separability assumption
Authors: Hemsley Elizabeth , Ardi Ibrahim , Rouvier Tony , Lacroix Simon , Carfantan Hervé , Monmayrant Antoine
Published: February 2022

We present a fast reconstruction algorithm for hyperspectral images, utilizing a small amount of data without the need for any training. The method is implemented with a dual disperser hyperspectral imager and makes use of spatial-spectral correlations by a so-called separability assumption that assumes that the image is made of regions of homogenous spectra. The reconstruction algorithm is simple and ready-to-use and does not require any prior knowledge of the scene. A simple proof-of-principle experiment is performed, demonstrating that only a small number of acquisitions are required, and the resulting compressed data-cube is reconstructed near instantaneously.
Requirement on the diurnal observation frequency for satellite remote sensing of photosynthetically available radiation
Authors: Ding Xiaosong , He Xianqiang , Bai Yan , Li Jiajia , Xu Yuzhuang , Wang Xiao , Zhu Qiankun
Published: February 2022

Photosynthetically available radiation (PAR) is essential for the photosynthesis processes of land plants and aquatic phytoplankton. Satellite observation with different diurnal frequencies (e.g., high frequency from geostationary satellites and low frequency from polar-orbit satellites) provides a unique technique to monitor PAR variation on large tempo-spatial scales. Owing to different climatic characteristics, different regions may require different observation frequencies to obtain accurate PAR estimation, but such requirements are still poorly known. Here, based on Advanced Himawari Imager (AHI) high-frequency (10-min) observation data from the geostationary satellite Himawari-8, we investigated the influence of diurnal observation frequency on the accuracy of PAR estimation and provided the minimal observing frequency to get high accurate PAR estimation in the AHI coverage area. Our results revealed a remarkable difference in the requirements for the diurnal observation frequency in both spatial and temporal distributions. Overall, high-latitude regions need a higher observing frequency than low-latitude areas, and winter half-years need higher observing frequency than summer half-years. These results provide a basis for designing satellites to accurately remote sensing of PAR in different regions.
All-optical pulse switching with a periodically driven dissipative quantum system
Authors: Han Yingying , Zhang Wenxian , Li Weidong
Published: February 2022

All-optical switching used to switch the input optical signals without any electro-optical conversion plays a vital role in the next generation of optical information processing devices. Even all-optical switchings (AOSs) with continuous input signals have been widely studied, all-optical pulse switchings (AOPSs) whose input signals are pulse sequences have rarely been investigated because of the time-dependent Hamiltonian, especially for dissipative quantum systems. In this paper, we propose an AOPS scheme, where a strong pulsed field is used to switch another pulsed input signal. With the help of Floquet-Lindblad theory, we identify the control field that can effectively turn on/off the input signal whose amplitude envelope is a square-wave (SW) pulse train in a three-level dissipative system. By comparing the properties of the AOPSs controlled by a continuous-wave (CW) field and an SW control field, we find that the SW field is more suitable to be a practical tool for controlling the input SW signal. It is interesting to impress that the switching efficacy is robust against pulse errors. The proposed protocol is readily implemented in atomic gases or superconducting circuits and corresponds to AOPSs or all-microwave pulse switchings.
Real-valued layer-based hologram calculation
Authors: Yasuki Daiki , Shimobaba Tomoyoshi , Makowski Michal , Suszek Jaroslaw , Sypek Maciej , Kakue Takashi , Ito Tomoyoshi
Published: February 2022

Layer-based hologram calculations generate holograms from RGB and depth images by repeating diffraction calculations using complex Fourier transforms (FTs). Holograms generated as such are suitable for near-eye display and can be easily reconstructed with good image quality, but they are computationally expensive because of multiple complex-valued operations, including complex FTs. In this study, we propose an acceleration method for layer-based hologram calculations by reducing time-consuming complex-valued operations using the real-valued FT and Hartley transform as real linear transformations. Real linear transformations transform real input data to real output data; thus, the proposed method generates amplitude holograms. Thus, we also propose a technique to convert holograms generated by real linear transformations into phase-only holograms using the half-zone plate process and digitalized single-sideband method while maintaining the calculation acceleration. The proposed method can speed up hologram calculations by a factor of around three while maintaining the same image quality as the conventional method.