bluuebunny/crossref_metadata_2025 huggingface dataset:
Efficacy and safety of PARP inhibitors (PARPi) with immune checkpoint inhibitors (ICI) in metastatic castration-resistant prostate cancer (mCRPC): A systematic review and single-arm meta-analysis.
Authors: Gazzoni Gabriela , Oliveira João Pedro , Reis Pedro Cotta Abrahão , Bittar Vinicius , Carvalho Bruno Murad , Vilbert Maysa , Stecca Carlos Eduardo
Published: June 2024

e17053

Background: Recent therapeutic advances in prostate cancer have allowed patients with metastatic disease to live longer and better, especially in the castration sensitive setting. Although improvements have been observed in the castration resistant space, survival in this setting remains suboptimal. Early-phase clinical trials suggest the combination of PARP inhibitors (PARPi) and immune checkpoint inhibitors (ICI) have synergistic effect by modulating the tumor microenvironment. In this systematic review and meta-analysis, we assessed the efficacy and safety of PARPi and ICI in the metastatic castration-resistant prostate cancer (mCRCP) setting. Methods: Pubmed, Cochrane and EMBASE were systematically searched from inception through December 10, 2023. Randomized and non-randomized clinical trials evaluating PARPi + ICI in mCRPC were included. PSA response rate (PSArr), radiographic progression-free survival (rPFS), objective response rate (ORR) and overall survival (OS) were analyzed. Subgroups according to (HRR) were assessed. We also pooled the prevalence of immune-related adverse events (irAE) and their corresponding 95% confidence intervals (95% CI). Statistical analysis was performed using R software version 4.3.2 and heterogeneity was evaluated through I2 statistics. Results: We screened 1070 reports, and six trials met the inclusion criteria (one phase III RCT and 5 phase I/II non-RCT), involving 799 participants. The overall ORR was 8.48% (95% CI 6.48-10.86 I2 0%). About 19% of patients achieved an PSArr (95% CI 9.51-32.50 I2 75%). Median OS was 15.8 months (95% IC 13.9-15.8), and rFPS was 4.5 months (95% IC 4.4-4.9). In patients harboring HRR mutations, PSArr was 17.53% (95% CI 10.43-27.95 I2 75), while in HRR non-mutated it was 10.49% (95% CI 5.89-17.99 I2 0%). The frequency of any-grade irAEs was 21.12% (95% CI 12.34-33.74 I2 85%), with 6.70% of grade 3-4 irAEs (95% CI 3.09-13.91 I2 80%). Hypothyroidism rate was 8.53% (95% CI 5.86-12.27 I2 29%) and adrenal insufficiency was 2.80% (95% CI 1.81-4.30 I2 0%). Conclusions: This meta-analysis results suggest that the combination of PARPi plus ICI in patients with mCRPC is safe and may benefit mainly patients with HRR mutations. Further studies in biomarker selected patients are needed. [Table: see text]
Real-world (RW) comparison of prostate-specific antigen (PSA) response in patients with de novo metastatic castration-sensitive prostate cancer (mCSPC) treated with apalutamide (APA) versus enzalutamide (ENZ).
Authors: Lowentritt Benjamin H , Khilfeh Ibrahim , Pilon Dominic , Du Shawn , Rossi Carmine , Kinkead Frédéric , Diaz Lilian , Ellis Lorie , Lefebvre Patrick , Brown Gordon Andrew
Published: June 2024

e17067

Background: Androgen receptor signaling inhibitor (ARSIs) treatment (APA or ENZ), in combination with androgen deprivation therapy (ADT) has improved the prognosis of patients with de novo mCSPC. PSA decline ≥90% (PSA90) after ARSI initiation has been associated with improved survival and delayed disease progression. The objective of this study was to compare PSA90 response at 6-months among next-generation ARSI-naïve patients with de novo mCSPC initiating APA or ENZ. Methods: Clinical data for US community urology practices from PPS Analytics was linked with claims data from Komodo Health Solutions Research Database. Included patients were assigned to exclusive cohorts based on the first APA or ENZ dispensation or pharmacy claim on or after 12/16/2019 (index date). Patients were also included if they had de novo mCSPC, identified if a metastatic diagnosis was observed ≤180 days after the initial prostate cancer (PC) diagnosis, ≥12 months of pre-index clinical activity, and ≥1 PSA measurement within 13-weeks pre-index. Follow-up spanned from index date until the earliest of index ARSI discontinuation (i.e., gap ≥90 days supply) or switch, radiopharmaceutical initiation, or end of clinical activity/data availability (9/30/2022). Pre-index characteristics (i.e., age, race, region, payer type, index year, time from metastasis, time from PC diagnosis, prior use of ADT, first-generation antiandrogen, or chemotherapy, metastasis locations, most recent PSA and testosterone level, and earliest Gleason score) were balanced between cohorts using inverse-probability of treatment weighting (IPTW). PSA90 was defined as the earliest ≥90% decline in PSA relative to most recent pre-index PSA. The proportion of patients achieving PSA90 was compared using a weighted Kaplan-Meier analysis and the time-to-PSA90 response was compared using a weighted Cox proportional hazards model. Results: Overall, 332 APA and 383 ENZ patients were identified. Patients’ pre-index characteristics were balanced using IPTW (Table). By 6 months post-index, 81.0% of APA and 75.2% of ENZ patients had ≥1 PSA test. PSA90 response at 6 months was achieved by a significantly higher proportion of APA patients, as compared to ENZ patients (62.8% vs 49.6%; p=0.004; Table). Median time to PSA90 response was 3.5 months for APA and 6.1 months for ENZ. Conclusions: This study of RW US data showed that a greater percentage of patients with de novo mCSPC treated with APA achieved a deep, early PSA response by 6 months as compared to those treated with ENZ. [Table: see text]
An NCDB demographic and socioeconomic analysis of mixed acinar ductal carcinoma.
Authors: Alban Sierra , Breytenbach Nicoline , Chang Amber , Reyes Jyztine , Silberstein Peter T. , Heise Craig , Hsia Beau
Published: June 2024

e17097

Background: Mixed acinar ductal carcinoma (MADC) is a rare form of prostate carcinoma with both acinar carcinoma and ductal adenocarcinoma components, originating in the prostate. Despite their infrequent occurrence, mixed carcinomas have demonstrated increasing prevalence in recent years and are associated with poor prognosis. This is especially concerning since prostate malignancies are one of the most common in men across the world. Thus, understanding the demographic patterns related to this malignancy can offer insight into its epidemiology, diagnosis, and relevant risk factors. The National Cancer Database (NCDB) was used to analyze these patterns in mixed acinar ductal carcinoma. Methods: A retrospective cohort analysis using data from the NCDB was performed for patients diagnosed with mixed acinar ductal carcinoma, ICD-O-3 Code 8552, between 2018 and 2020 (N = 206). Demographic factors were analyzed using descriptive statistics, including age, sex, race, Hispanic heritage, type of facility, distance from facility, and Charles/Deyo score. Statistical regression analysis was used to evaluate incidence patterns. Results: Between 2018 and 2020, 206 patients with a MADC diagnosis were identified with a gradually increasing incidence of diagnosis (R² = 0.2276). Of this cohort, an overwhelming majority identified as male (98.5%) and of White (83%) and non-Hispanic (95.6%) origin. The majority of patients (54.4%) received coverage from Medicare and another 39.5% were under private insurance/managed care. The most common primary site was the prostate (95.1%). NCDB Analytic Staging was not applicable in most cases (82%) and most individuals had a total Charlson-Deyo comorbidity score of 0 (77.2%). The average age at diagnosis was 67.2 years (SD = 8.6, range = 43 – 90 years). Most patients (84.0%) received surgery; following resection of the primary tumor, over half of these patients (53.4%) had no residual tumor. Many of the patients (97.4%) survived at least thirty days after primary surgery, with a similar survival rate (94.9%) after ninety days. The estimated two-year survival rate was 93.9% and the mean survival after diagnosis was 43.2 months (3.6 years). Conclusions: Based on our literature searches, this is the first analysis using NCDB data for mixed acinar ductal carcinoma addressing the lack of understanding of the demographic aspects of the disease. MADC patients were mostly White and non-Hispanic males. Most of these patients held Medicare as a primary insurance, likely due to the overall older population impacted by this cancer. MADC primarily affected the prostate and the patients typically had a favorable prognosis following surgery of the primary site. Additional investigations are necessary to determine the effects of these socioeconomic and demographic factors on individuals with mixed acinar ductal carcinoma.
Investigating L1CAM and β-catenin as prognostic indicators in fertility-sparing endometrial cancer treatment.
Authors: Park Jeong-Yeol , Kang Ok-Ju , Jo Uiree
Published: June 2024

e17582

Background: Fertility-sparing progestin therapy is well-known treatment option for young women with endometrium-confined, low-grade, endometrioid type endometrial cancer (EC). The introduction of a molecular diagnostic framework by the TCGA Research Network in 2013, categorizing tumors into four prognostic groups, has significantly influenced the prognosis prediction in EC. The ProMisE system further stratifies EC based on molecular profiles, highlighting the need for refined prognostic tools, especially for those undergoing conservative treatments. Our study aims to explore the effectiveness of ProMisE and various immunohistochemical (IHC) markers in predicting outcomes for more fertility-sparing progestin therapy in endometrial cancer. Methods: We included young EC patients treated with fertility-sparing progestin therapy at a single center between January 2011 and December 2020. Patients were categorized according to the results of IHC staining to detect mismatch repair (MMR) proteins and p53 and the results of DNA polymerase epsilon (POLE) mutations which were identified through hotspot sequencing with droplet digital polymerase chain reaction like ProMisE classification. We also measured L1CAM, β-catenin, ER, and PR expression levels through IHC staining. The Complete Response (CR) rate to progestin therapy and PFS after progestin therapy were analyzed between each biomarker-driven subgroup. Results: Out of 104 patients, 60 patients (57.7%) were treated with MPA alone, while 44 patients (42.3%) received a combination of MPA and LNG-IUS. The CR was observed in 64 patients (61.5%). Among those achieving CR, 31 patients (48.4%) experienced recurrence over a median follow-up period of 54.7 months (range:10-128 months). The 5-year PFS was recorded at 67.2%, and the 5-year OS was maintained at 100%. Each one patient showed a POLE mutation, MMRd, and P53 abnormality, leaving 101 (97.1%) with NSMP. IHC revealed L1CAM expression in 12 patients (11.5%) and dual membranous and nuclear β-catenin expression in 8 patients (7.7%). This β-catenin expression significantly correlated with higher CR rates (71.4% vs. 45.6%, p=0.022), while L1CAM presence significantly reduced PFS (3yr-PFS 28.6% vs. 53.9%, p=0.033). Conclusions: Almost all endometrium-confined, low-grade, endometrioid type EC were categorized to NSMP, so that molecular classification had little role in young women who received fertility-sparing progestin therapy. Rather, β-catenin emerges as a positive predictive biomarker for CR, and L1CAM as a negative prognostic biomarker for PFS in this treatment setting. This supports incorporating these IHC markers into molecular classifiers like ProMisE for enhanced risk stratification and personalized treatment in this disease setting.
Differential gene expression analysis of a phase II randomized clinical trial of patients with endometrial cancer (EC) treated with megestrol acetate ± pterostilbene.
Authors: Dellinger Thanh Hue , Wu Xiwei , Cho Hyejin , Yost Susan Elaine , Ruel Nora H. , Invernizzi Marta , Senguttuvan Rosemary Noel , Frankel Paul Henry , Kebria Mehdi , Han Ernest Soyoung , Song Mihae , De Leon Maria , Eng Melissa , Tinsley Raechelle , Schmolze Daniel , Chang Sue , Arias Stella Javier
Published: June 2024

e17601

Background: The oral antioxidant pterostilbene (PT) (3,5-dimethoxy-40-hydroxystilbene) has demonstrated synergistic antiproliferative effect with megestrol acetate (MA) in endometrial cancer (EC). We conducted a preoperative (window of opportunity) study enrolling endometrial cancer patients scheduled for hysterectomy, who were randomized to preoperative PT+MA vs MA alone. Methods: This prospective, randomized phase II clinical trial (NCT03671811) enrolled patients who were surgical candidates for hysterectomy. Patients were randomized 1:1 to each arm and were treated for 3 weeks with either PT+MA (arm 1) or MA alone (arm 2). Exploratory objectives included histologic response by GOG 211 criteria, and transcriptional changes using whole transcriptome analysis. For the RNA-seq analysis, differential expression analysis used the “limma” R limma package. The differentially expressed genes were selected based on the cutoff values of p-value <= 0.05 and fold change >= 1.5. The gene set enrichment analysis was performed using GSEA software v. 4.3.2 to identify the affected Hallmark and KEGG pathways, using the pre-ranked gene list ranked by the -log10(p-value) with a sign determined by the fold change direction. Results: This prospective, randomized phase II clinical trial (NCT03671811) enrolled patients who were surgical candidates for hysterectomy. Patients were randomized 1:1 to each arm and were treated for 3 weeks with either PT+MA (arm 1) or MA alone (arm 2). Exploratory objectives included histologic response by GOG 211 criteria, and transcriptional changes using whole transcriptome analysis. For the RNA-seq analysis, differential expression analysis used the “limma” R limma package. The differentially expressed genes were selected based on the cutoff values of p-value <= 0.05 and fold change >= 1.5. The gene set enrichment analysis was performed using GSEA software v. 4.3.2 to identify the affected Hallmark and KEGG pathways, using the pre-ranked gene list ranked by the -log10(p-value) with a sign determined by the fold change direction. Conclusions: In endometrial cancer, the oral antioxidant Pterostilbene increases innate immune system pathway expression, while reducing mTOR pathway expression, potentially serving as a useful adjunct to progestin hormonal therapy in EC. Clinical trial information: NCT03671811 .
Genomic profiling of Chinese patients with endometrial adenocarcinoma (EA).
Authors: Huiming Guo , Yuni Jin , Liangdi Su , Yuan Liu , Chan Bao , Tian Li , Juan Zhang , Zhang Bei
Published: June 2024

e17606

Background: Incidences of endometrial adenocarcinoma are increasing in the Chinese with poor prognosis. Our aim was to explore the genomic profiling of Chinese endometrial adenocarcinoma and whether they could provide potential prognostic and therapeutic implications. Methods: Between January 2019 and August 2023, a total of 204 samples, were obtained from Chinese EA patients at the 3DMed Biobank (Shanghai, China) and The First Affiliated Hospital of Kunming Medical University. Genomic alterations were determined using NGS 733 cancer-related genes panel. TMB-H was defined as above 10 mutation/Mb. Positive PD-L1 expression was defined as ≥1 of CPS. Statistical analyses were performed using R version 3.4.4. Results: A total of 204 patients with EA were included in this study. The median age at diagnosis was 56 (range, 27-92) years old. Among these 204 tissue samples, 178 (87%) were collected from primary lesions. 9.0 %( 12/133) patients exhibited positive PD-L1 CPS status. 19.6% of patients in our cohort exhibited MSI. Median TMB was 6.15 mutation/Mb [0, 473], and 33.8% patients had TMB-H status. In this cohort, a total of 9404 somatic alterations were detected in 96.1% of the patients (196/204), with an average of 46 alterations per patient. The most commonly alternated genes were PTEN (68%), ARID1A (50%), PIK3CA (47%), PIK3R1 (32%), TP53 (31%), ZFHX3 (30%), CTCF (25%), KMT2C (23%), KRAS (22%), CTNNB1 (22%), CHD4 (18%), FAT4 (18%), FAT1 (18%), NCOR2 (17%), ARID1B (17%), AR (16%), BCOR1 (16%), MYC (16%), and NF1 (16%). The hotspot mutations (prevalence higher than 2%) in Chinese EA included PTEN p. R130G, PIK3CA p.R88Q, RNF43 p.G659Vfs*41, PIK3CA p.H1047R, KMT2C p.K2797Rfs*26, CTCF p.T204Nfs*26, KRAS p.G12D, and TEAD2 p.H295Mfs*12. In terms of structural-rearrangements, ten fusions were detected in six genes, with NOTCH2 (n = 4) and RAF1 (n = 2) having the highest number of events. In terms of CNVs, frequently affected genes in Chinese EA included PTEN (249), ARID1A (172), PIK3CA (137), ZFHX3 (110), LRP1B (96), and FAT4 (93). The frequently affected pathways were PI3K (88%), RTK-RAS (72%), and WNT (54%) Furthermore, pathogenic or likely pathogenic germline variants were observed in 33 patients (16.2%). The affected genes included MSH6 (6), MLH1 (4), MSH2 (4), ATM (3), FANCA (3), BRCA2 (3), BRCA1 (2), PMS2 (2), APC (1), BARD1 (1), BLM (1), CDH1 (1), FANCD2 (1), FANCG (1), PALB2 (1), RAD50 (1), RAD54L (1), and RECQL4 (1). Conclusions: In summary, we presented the large-scale genomic profiling of EA in the Chinese population and demonstrated emphasizes the importance of molecular characterization in facilitating clinical decision-making and improving patient outcomes in EA.
Phase 2 trial for sequential treatment of high dose cabozantinib (CABO) or CABO plus nivolumab (NIVO) on/after progression on CABO monotherapy in advanced renal cell carcinoma (RCC): Seq-Cabo.
Authors: Qin Qian , Brugarolas James , Hammers Hans J. , Arafat Waddah , Courtney Kevin Dale , Wang Jue , Jiang Changchuan , Zhang Song , Cowey Charles Lance , Hutson Thomas E. , Zhang Tian
Published: June 2024

TPS4609

Background: Efficacy outcomes for advanced RCC have improved with vascular endothelial growth factor receptor (VEGFR)-tyrosine kinase inhibitors (TKI) and immune checkpoint inhibitors (IO), and CABO has become an established treatment for both front-line and refractory, advanced RCC. However, most patients develop resistance to CABO. With each subsequent line of therapy, efficacy and survival benefits also shorten and treatment options become limited. It is thus important to explore ways to maximize each line of therapy. Methods: Based on previous studies suggesting 1) dose-dependent effect of VEGFR-TKIs with feasibility/efficacy of CABO dose escalation to 80mg and 2) immune-modulatory effects of CABO, we have designed a two-cohort phase 2 trial to salvage CABO response, either by escalating the dose of CABO to 80mg oral (PO) daily (cohort 1) or by combining CABO 40mg PO daily with NIVO 480mg intravenous (IV) every 4 weeks (cohort 2), based on investigator choice. Subjects will be treated until progression or unacceptable toxicity. Main inclusion criteria include progressive advanced RCC after prior CABO monotherapy for at least 6 months, able to tolerate CABO 60mg PO daily (cohort 1) and 40mg PO daily (cohort 2), radiographically measurable disease, ECOG < 2, and adequate end-organ function. Main exclusion criteria include prior treatment with concurrent CABO/NIVO, uncontrolled co-morbidities, uncontrolled HIV, and concurrent malignancy (excepting completely excised skin cancers and organ-confined Gleason 6 prostate cancer). Primary endpoint is progression free survival (PFS) with key secondary endpoints including overall response rate, disease control rate, duration of response, and overall survival. The null hypothesis of median PFS 3 months will be tested against an alternative hypothesis of median PFS 6 months. Assuming a 2-sided significance level of 10% and 80% power, and estimating 10% drop out, 18 patients per cohort (36 patients total) will be enrolled.Pharmacokinetics, circulating biomarkers, and pre-/post-biopsies are planned for tissue-based analyses. The study is open for enrollment (NCT05931393). Clinical trial information: NCT05931393 .
A phase II study of lurbinectedin with or without avelumab in small cell carcinoma of the bladder (LASER).
Authors: Simon Nicholas I. , Chandran Elias , Niglio Scot Anthony , Kydd Andre Rashad , Atiq Saad Omar , Ley Lisa , Wang Tzu-fang , Boudjadi Salah , Smith Elizabeth , Akbulut Dilara , Steinberg Seth M. , Apolo Andrea B
Published: June 2024

TPS4629

Background: Small cell carcinoma of the bladder (SCCB) is a rare, aggressive malignancy accounting for <1% of all bladder malignancies. Given its rarity, few prospective randomized trials have been completed in SCCB. Most therapeutic evidence comes from retrospective case series and due to its histologic similarity to small cell lung cancer (SCLC), current guidelines recommend bladder cancers with any component of small cell histology be treated similarly to SCLC. Lurbinectedin is a novel alkylating agent which recently received accelerated approval from the FDA as a second line treatment for SCLC after demonstrating an overall response rate (ORR) of 35.2% and median duration of response (DoR) of 5.3 months (Trigo et al., Lancet Oncol, 2020). Avelumab is an anti-PD-L1 antibody FDA approved as maintenance treatment for patients with locally advanced or metastatic urothelial cancer (UC) without progression on frontline chemotherapy. Case reports have demonstrated that second line options in SCLC, including immunotherapy, appear to have some efficacy in SCCB. The purpose of this study is to assess the efficacy of lurbinectedin, either alone or in combination with avelumab, in participants with SCCB or other high grade neuroendocrine tumors (HGNETs) of the urinary tract. Methods: LASER (NCT06228066) is a phase II, multisite, open label, nonrandomized study with two cohorts. Eligible patients must have pathologically confirmed SCCB or other HGNETs of the urinary tract. Patients with mixed histologies, with any component of neuroendocrine tumor, are eligible. Patients must have received or be ineligible/refused frontline platinum/etoposide therapy. Participants in Cohort 1 must have received prior immune checkpoint inhibitors (ICIs) or be ineligible for treatment with ICI. These patients will receive lurbinectedin 3.2mg/m2 IV every 21 days. Participants in Cohort 2 must be ICI naïve but eligible to receive them. These patients will receive lurbinectedin 3.2mg/m2 IV and avelumab 800mg IV every 21 days. The primary endpoint for both cohorts is ORR, with key secondary endpoints including clinical benefit rate, PFS, OS, and DoR. The study will be conducted using a Simon minimax two stage design to rule out an ORR of 5% in favor of an ORR of 25% or greater in each cohort. If 1 of the first 12 patients has a response accrual will continue up to 16 evaluable patients per cohort. Accrual ceiling will be set at 35 patients. Exploratory objectives include analyzing peripheral immune subsets, DNA and RNA sequencing of tumors, and measurement of ctDNA and CTCs. Clinical trial information: NCT06228066 .
SAVE: A prospective, single-arm, single-center clinical study of disitamab vedotin in combination with toripalimab in patients with advanced penile cancer that has progressed or is intolerant to cisplatin chemotherapy.
Authors: Yuan Fang
Published: June 2024

TPS5107

Background: At present, penile cancer patients receiving chemotherapy with paclitaxel, ifosfamide and cisplatin or docetaxel, cisplatin and 5-fluorouracil have a lack of post-progression treatment, and some patients lose the opportunity for effective treatment due to inability to tolerate chemotherapy. Even though the epidermal growth factor receptor (EGFR) is ubiquitously expressed in penile squamous cell carcinoma, anti-EGFR-targeted drugs have not achieved significant survival benefit. Immune checkpoint inhibitors (ICIs) have achieved "de-tumor immune escape", and a small number of penile cancer cases have shown reactivity. However, only patients with high TMB, high PD-L1 expression, or MSI-H have benefited from ICIs. Antibody-drug conjugates (ADCs) have advanced rapidly in recent years, and HER2-targeted ADCs have shown significant efficacy in HER2-overexpressing urothelial carcinoma. HER2 ADC and ICI can simultaneously block HER2 and PD-1/PD-L1 signaling pathways, bridge PD-1-expressing T lymphocytes and HER2-expressing tumor cells, assist T cells to recognize and kill tumor cells, improve immunosuppression in the tumor microenvironment, and enhance the infiltration of immune cells into tumors. Recent cytology and animal studies have also shown that HER2-targeted ADCs exhibit significant anti-tumor activity in both HER2-positive and cisplatin-resistant penile cancers. Therefore, in order to explore the feasible and effective options for patients with advanced penile cancer who have progressed or are intolerant to cisplatin-based chemotherapy, a single-arm, single-center clinical study using Disitamab Vedotin combined with Toripalimab is proposed. Methods: About 20 patients with advanced penile cancer who have progressed or are intolerant to chemotherapy are planned to be enrolled with antibody-drug conjugates (Disitamab Vedotin for injection, 1 time/2 weeks, 2.0 mg/kg) and PD-1 (Toripalimab, 1 time/2 weeks, 3.0 mg/kg; or1 time/3 weeks, 240 mg/kg), regimen until the disease progresses or is intolerant. This study is expected to provide a basis for the treatment of advanced penile cancer using this regimen.
A randomized phase II study of ADT + abiraterone versus ADT + abiraterone + docetaxel in patients with low-volume metastatic hormone-sensitive prostate cancer.
Authors: Fenton Sarah Elizabeth , Kocherginsky Masha , VanderWeele David James , Hussain Maha H. A.
Published: June 2024

TPS5121

Background: The PEACE-1 and ARASENS phase III trials showed benefit of “triplet” therapy in patients with metastatic hormone sensitive prostate cancer (mHSPC). Triplet therapy is defined as androgen deprivation therapy (ADT), docetaxel and an androgen receptor signaling inhibitor. Both trials showed improved outcomes in patients with a high volume of disease per CHAARTED criteria (≥ 4 bone lesions with ≥1 beyond the axial skeleton or visceral metastasis). The benefit was less clear in patients with low volumes of disease, this may be due to the use of docetaxel as the control arm in this patient population. In the CHAARTED study the benefit of docetaxel in addition to ADT was most pronounced in patients with high volume mHSPC, and the benefit was less certain in low volume disease. To address this uncertainty, we are conducting this phase II trial evaluating ADT/abiraterone versus ADT/abiraterone plus docetaxel in patients with low volume mHSPC. Methods: This is a multisite, randomized trial of ADT (physician’s choice) and abiraterone (1000mg daily + 5 mg prednisone) versus ADT, abiraterone and docetaxel (75 mg/m2 q3 weeks for 6 cycles). Patients may have started ADT up to 12 weeks prior to randomization. Key eligibility criteria include a tissue-confirmed diagnosis of prostate cancer (PCa) and evidence of metastatic disease on CT, MRI and/or bone scan that meets CHAARTED criteria for low volume disease. Recurrent PCa and exposure to ADT prior to the diagnosis of metastatic disease are allowed, as is concurrent treatment with radiation therapy. The primary objective is to assess and compare radiographic progression free survival (rPFS) between treatment arms. Power calculations assume the median rPFS of the control arm is 33 months (based on the LATITUDE trial) versus 55 months in the docetaxel arm (based on the PEACE-1 trial). A sample size of 120 patients will provide 80% power with a one-sided α = 0.10 Type I error rate based on the log rank test to detect a hazard ratio = 0.60. Assuming a 36-month accrual duration and an additional 3 years of follow up, a total of 70 events are expected to occur on this study. The study will enroll 150 patients (75 per arm) to obtain 120 evaluable patients (assuming a 20% attrition rate). Secondary endpoints include overall survival, PSA response rate, overall response rate, time to castration resistant PCa and time to initiation of subsequent anti-neoplastic therapy. Exploratory endpoints include quality of life assessments and rates of adverse events. Enrollment in this trial began in Dec 2023. It is open at the Robert H. Lurie Comprehensive Cancer Center of Northwestern University and other satellite sites affiliated with Northwestern University. Clinical trial information: NCT06060587 .
Psychosocial Stress Trajectories Are Associated With Puberty Timing: Findings From a 7-Year Cohort in Chongqing, China
Authors: Liu Shudan , Zhou Yangxue , Wu Di , Tian Yu , Luo Jie , Zhang Jie , Wang Wenhe , Yan Ge , Liu Qin
Published: June 2024

Context

Evidence for the associations between psychosocial stress PS related exposures and puberty timing are inconclusive. The PS of children has rarely been evaluated through repeated measurements.

Objective

To evaluate the associations between PS trajectories and pubertal outcomes of girls and boys in a Chinese cohort (2015-2022).

Methods

Pubertal outcomes of 732 girls and 688 boys were physically examined every 6 months. Stressful life events were repeatedly assessed 7 times. A group-based trajectory model was fitted for the optimum trajectories of total PS and PS from 5 sources. A Cox model adjusted for age, body mass index, and socioeconomic factors was used to evaluate the association.

Results

Compared with the “low, gradual decline” trajectory, the “moderate, gradual decline” trajectory of total PS was associated with late menarche (hazard ratio [HR] 0.816, 95% CI 0.677-0.983), late pubic hair development (HR 0.729, 95% CI 0.609-0.872), and late axillary hair development (HR 0.803, 95% CI 0.661-0.975) in girls. Girls following the “high, rise then decline” trajectory of PS from family life demonstrated delayed axillary hair development (HR 0.752, 95% CI 0.571-0.990). For boys, the “high, rise then decline” trajectory of PS from academic adaptation (HR 0.670, 95% CI 0.476-0.945) and life adaptation (HR 0.642, 95% CI 0.445-0.925) was associated with late axillary hair development. Boys in the “moderate, gradual decline” trajectory of PS from peer relationships was at risk of early testicular development (HR 1.353, 95% CI 1.108-1.653).

Conclusion

Chronic PS may be associated with delayed onset of several pubertal signs in both girls and boys. It may also accelerate testicular development of boys, indicating its varying impact on pubertal timing during early and later stages.
Expiratory Central Airway Collapse and Dynamic Hyperinflation During Peroral Endoscopic Myotomy: A Case Report
Authors: Nielsen Emma I. , Tresierra Steve , Cenkowski Marta , Bechara Robert , Klar Gregory , Mizubuti Glenio B.
Published: June 2024

In tracheobronchomalacia, the structural weakening of the airway results in altered ventilatory mechanics. This case report describes a patient with known tracheobronchomalacia who experienced expiratory central airway collapse and dynamic pulmonary hyperinflation during peroral endoscopic myotomy (POEM) to treat symptomatic achalasia. We discuss the physiological considerations and potential complications of a POEM procedure with superimposed tracheobronchomalacia and present perioperative strategies for the prevention and management of this potentially deleterious combination. Although tracheobronchomalacia was a known condition in our patient, it is likely an underdiagnosed condition that may first present intraoperatively.
The Thrill of Becoming
Authors: Tian Xiaofei
Published: June 2024

What is the politics of form in the changing political climate? How does the writing of old-style poetry (jiuti shi) and new-style or modern vernacular poetry (xin shi) fare in digital times? As the internet, computers, smartphones, and Chinese internet poetry continue to evolve, how do these ongoing manifestations and technological transformations impact the landscape of poetry writing, and how do researchers answer these new challenges? This essay sketches the trajectory of change of modern old-style poetry and new-style poetry in response to the changing times and to each other, discusses how these changes embody larger cultural shifts, and addresses the role played by scholars and critics in the process. It argues that the gap between old-style poetry and new-style poetry is closing in interesting ways, and that scholarship on modern poetry is not about deciding the literary canon or predicting what comes next, but about constantly adjusting our understanding in the eternal process of becoming and realizing that the past is also changing owing to the changing perspective of the present.
Gaming Sinographs beyond the Ludic
Authors: O'Krent Michael
Published: June 2024

This article rethinks the notion of the Sinophone through digital technology by using the Taiwanese videogame Word Game (Wenzi youxi, Team9, 2022) as a case study. The digital Sinophone sees Chineseness as an act of positive identification claimed by engaging with digital artifacts; it defines a single mass audience coterminous with the Sinophone cultural sphere. Word Game constructs a two-dimensional space in which all objects are composed of sinographs, requiring the player to possess extensive knowledge of the construction of and relationship between sinographs according to Chinese grammatical and semiotic uses in order to progress in the game. Contrary to the internationalizing tendencies of the videogame market and the long history of tension between sinographic writing and the typographical technologies of technological modernity, the result is a uniquely Sinophone videogame. In Word Game, the logic of gameplay mechanics consists not of mathematical universals but culturally determined relationships between sinographs. The article concludes by examining the implications for the interdisciplinary study of videogames. Whereas contemporary videogame studies seeks to situate video gaming in broader cultural discourses, a culturalist view of videogames sees game mechanics as cocreators of culture rather than a mirror of culture.
Writing the Heart Sutra Online
Authors: Vermeeren Laura
Published: June 2024

Online calligraphic handwriting has taken on various creative forms: from WeChat handwriting communities to digital teaching apps and downloadable calligraphic fonts. This article proposes to consider online calligraphy practice a means to connect to an imagined past. Calligraphy, then, is employed for a haptic reconnecting with the past through movements of brush and wrist by restoring and reenacting an (imagined) classical Chinese culture on digital screens. This article focuses specifically on the affective modes of writing the Heart Sutra (Xin Jing 心經) in the online environment of the platform Kuaishou (快手). It analyzes how the affordances of the social media platform allow for various forms of affective engagement with the classicist text. This article suggests that the specific modalities underpinning Heart Sutra writings are informed by the nostalgic desire to perform a type of Chineseness. Instances of online sutra writings on Kuaishou further contest the widespread misconception that content uploaded on the specific platform is mostly subsumable under the cultural mode of tuwei 土味 or “vulgar content.”
Climate change consequences on the systemic heart of female Octopus maya: oxidative phosphorylation assessment and the antioxidant system
Authors: Meza-Buendia Ana Karen , Aparicio-Trejo Omar Emiliano , Díaz Fernando , Pedraza-Chaverri José , Álvarez-Delgado Carolina , Rosas Carlos
Published: June 2024

There is evidence that indicates that temperature modulates the reproduction of the tropical species Octopus maya, through the over- or under-expression of many genes in the brain. If the oxygen supply to the brain depends on the circulatory system, how temperature affects different tissues will begin in the heart, responsible for pumping the oxygen to tissues. The present study examines the impact of heat stress on the mitochondrial function of the systemic heart of adult O. maya. The mitochondrial metabolism and antioxidant defense system were measured in the systemic heart tissue of female organisms acclimated to different temperatures (24, 26, and 30°C). The results show that acclimation temperature affects respiratory State 3 and State 4o (oligomycin-induced) with higher values observed in females acclimated at 26°C. The antioxidant defense system is also affected by acclimation temperature with significant differences observed in superoxide dismutase, glutathione S-transferase activities, and glutathione levels. The results suggest that high temperatures (30°C) could exert physical limitations on the circulatory system through the heart pumping, affecting nutrient and oxygen transport to other tissues, including the brain, which exerts control over the reproductive system. The role of the cardiovascular system in supporting aerobic metabolism in octopus females is discussed.
Re-assessment of the subcellular localization of Bazooka/Par-3 in Drosophila: no evidence for localization to the nucleus and the neuromuscular junction
Authors: Kim Soya , Shahab Jaffer , Vogelsang Elisabeth , Wodarz Andreas
Published: June 2024

Bazooka/Par-3 (Baz) is an evolutionarily conserved scaffold protein that functions as a master regulator for the establishment and maintenance of cell polarity in many different cell types. In the vast majority of published research papers Baz has been reported to localize at the cell cortex and at intercellular junctions. However, there have also been several reports showing localization and function of Baz at additional subcellular sites, in particular the nuclear envelope and the neuromuscular junction. In this study we have re-assessed the localization of Baz to these subcellular sites in a systematic manner. We used antibodies raised in different host animals against different epitopes of Baz for confocal imaging of Drosophila tissues. We tested the specificity of these antisera by mosaic analysis with null mutant baz alleles and tissue-specific RNAi against baz. In addition, we used a GFP-tagged gene trap line for Baz and a bacterial artificial chromosome (BAC) expressing GFP-tagged Baz under control of its endogenous promoter in a baz mutant background to compare the subcellular localization of the GFP-Baz fusion proteins to the staining with anti-Baz antisera. Together, these experiments did not provide evidence for specific localization of Baz to the nucleus or the neuromuscular junction.
Clutter resilience via auditory stream segregation in echolocating greater mouse-eared bats
Authors: Pedersen Michael B. , Beedholm Kristian , Hubancheva Antoniya , Koseva Kaloyana , Uebel Astrid S. , Hochradel Klaus , Madsen Peter T. , Stidsholt Laura
Published: June 2024

Bats use echolocation to navigate and hunt in darkness, and must in that process segregate target echoes from unwanted clutter echoes. Bats may do this by approaching a target at steep angles relative to the plane of the background, utilizing their directional transmission and receiving systems to minimize clutter from background objects, but it remains unknown how bats negotiate clutter that cannot be spatially avoided. Here, we tested the hypothesis that when movement no longer offers spatial release, echolocating bats mitigate clutter by calling at lower source levels and longer call intervals to ease auditory streaming. We trained five greater mouse-eared bats (Myotis myotis) to land on a spherical loudspeaker with two microphones attached. We used a phantom-echo setup, where the loudspeaker/target transmitted phantom clutter echoes by playing back the bats' own calls at time delays of 1, 3 and 5 ms with a virtual target strength 7 dB higher than the physical target. We show that the bats successfully landed on the target, irrespective of the clutter echo delays. Rather than decreasing their source levels, the bats used similar source level distributions in clutter and control trials. Similarly, the bats did not increase their call intervals, but instead used the same distribution of call intervals across control and clutter trials. These observations reject our hypothesis, leading us to conclude that bats display great resilience to clutter via short auditory integration times and acute auditory stream segregation rather than via biosonar adjustments.
Passive elasticity properties of Octopus rubescens arms
Authors: Halder Udit , Gribkova Ekaterina D. , Gillette Rhanor , Mehta Prashant G.
Published: June 2024

In this report, passive elasticity properties of Octopus rubescens arm tissue are investigated using a multidisciplinary approach encompassing biomechanical experiments, computational modeling, and analyses. Tensile tests are conducted to obtain stress–strain relationships of the arm under axial stretch. Rheological tests are also performed to probe the dynamic shear response of the arm tissue. Based on these tests, comparisons against three different viscoelasticity models are reported.
Loss of ADAR1 protein induces changes in small RNA landscape in hepatocytes
Authors: Roučová Kristina , Vopálenský Václav , Mašek Tomáš , del Llano Edgar , Provazník Jan , Landry Jonathan J.M. , Azevedo Nayara , Ehler Edvard , Beneš Vladimír , Pospíšek Martin
Published: June 2024

In recent years, numerous evidence has been accumulated about the extent of A-to-I editing in human RNAs and the key role ADAR1 plays in the cellular editing machinery. It has been shown that A-to-I editing occurrence and frequency are tissue-specific and essential for some tissue development, such as the liver. To study the effect of ADAR1 function in hepatocytes, we have created Huh7.5 ADAR1 KO cell lines. Upon IFN treatment, the Huh7.5 ADAR1 KO cells show rapid arrest of growth and translation, from which they do not recover. We analyzed translatome changes by using a method based on sequencing of separate polysome profile RNA fractions. We found significant changes in the transcriptome and translatome of the Huh7.5 ADAR1 KO cells. The most prominent changes include negatively affected transcription by RNA polymerase III and the deregulation of snoRNA and Y RNA levels. Furthermore, we observed thatADAR1KO polysomes are enriched in mRNAs coding for proteins pivotal in a wide range of biological processes such as RNA localization and RNA processing, whereas the unbound fraction is enriched mainly in mRNAs coding for ribosomal proteins and translational factors. This indicates that ADAR1 plays a more relevant role in small RNA metabolism and ribosome biogenesis.
Effect of different surface treatments on the repair bond strength between aged and new alkasite based restorative material
Authors: Purayil Tina Puthen , Ginjupalli Kishore , Pentapati Kalyana , Dureja Aastha , Nayak Rashmi
Published: June 2024

Background This study investigates various surface treatment methods to assess shear bond strength between set Cention N (alkasite-based restorative material) and new alkasite based restorative material. Assessing different surface treatments provide insights in optimizing repair procedure that enables durability of the restoration, thus potentially benefitting clinical outcomes. Methods A total of 48 alkasite based restorative material blocks, measuring 4 mm in depth and 4 mm in diameter, were prepared. The samples were randomly divided into 8 groups (n = 6) according to the surface treatment done. Group I: Surface preparation by bur; Group II: Surface treatment by laser; Group III: Application of 2-step etch and rinse adhesive (Adper Single Bond 2 adhesive),Group IV: Application of single step self-etch adhesive (Scotchbond Universal adhesive); Group V: Bur preparation followed by application of 2-step etch and rinse adhesive; Group VI: Bur preparation followed by application of single step self-etch adhesive; Group VII: Laser preparation followed by application of 2-step etch and rinse adhesive; and Group VIII: Laser preparation followed by application of single step self-etch adhesive. Post-surface preparation, all the specimens were restored with newly mixed alkasite material. Repair bond strength measurements were assessed with universal testing machine. Shapiro-Wilk and Levene's tests were used to check normality and Homogeneity of variance. ANOVA with post-hoc Games-Howell test and two-way ANOVA with post-hoc Bonferroni test was performed to evaluate the influence of surface preparation on the repair bond strength. Results Using a 2-step etch and rinse adhesive resulted in a higher repair bond strength (26.05±2.12) compared to other surface treatments. In contrast, roughening of the surface with burs led to lowest repair bond strength (17.06±3.29) (P=0.02). Conclusion Application of 2-step etch and rinse adhesive to the existing alkasite based restorative material provides superior bonding with the newly added alkasite based restorative material.
Decision-making based on Markov decision process in integrated artificial reasoning framework—Part 2: Applications
Authors: Warns Kyle , Kim Junyung , Wang Xinyan , Zhao Xingang , Phathanapirom Birdy , Golay Michael W. , Kang Hyun Gook
Published: June 2024

To address the challenge of interpreting the decisions made by machine learning-based control algorithms, the Integrated Artificial Reasoning Framework (IARF) introduced in Part I of this work was developed. Further implementing this framework within a Markov Decision Process (MDP) yielded a decision-making system which produces optimal decisions whose logic can be easily traced and understood. The IARF with MDP formulated in Part I of this study was applied to two case studies of relevance to the nuclear power community: 1) operational decision-making while experiencing the degradation of key components, and 2) optimal control of a nuclear power and hydrogen co-generation facility. This work details the steps of implementing and analyzing these two studies, beginning with the creation of simulation models using the Modelica programming language, covering the formulation of the MDP using the IARF, and concluding with the execution and analysis of the scenarios. Technical challenges related to implementation, such as maintaining physically understandable traceability and efficiently producing large amount of data for calculating state transition probabilities, are addressed and their resolutions are suggested. Emphasis is placed on the benefits of relying on a replaceable modeling framework for simulating system behavior. Results indicate that optimal operational trajectories were successfully found by the MDP, and through utilization of the IARF, these results are easily interpretable and understandable to any user.
CFD model for predicting spent nuclear fuel drying conditions
Authors: Islam Fakhrul , Cooper Nathaniel , Abboud Alexander W. , Farouk Tanvir , Khan Jamil , Guillen Donna Post , Knight Travis
Published: June 2024

Background A significant quantity of aluminum-clad spent nuclear fuel (ASNF) is currently managed by the United States (U.S.) Department of Energy (DOE) at several sites in the U.S. Much of this fuel develops a corrosion layer with adsorbed water either through pre-corrosion, in-reactor, or in wet storage depending on the source. Gamma radiation from the fuel after removal from the reactor can cause evolution of hydrogen from this corrosion layer. For long-term safety it is desirable to remove the adsorbed water from the fuel surface to limit the production of hydrogen gases when the fuel is placed in road-ready sealed canisters for eventual final disposition. Methods This study presents a series of experiments showing the effectiveness of both forced helium drying and vacuum drying methods for the removal of water from surrogate fuel assemblies. A computational fluid dynamics (CFD) model is constructed to replicate the drying processes and simulate the experiments. Results The model suggests that increasing the inlet temperature is a more efficient way of improving the efficacy of a drying process. An increase in inlet temperature leads to a reduction in drying time 28–55% greater than the same relative increase in flow rate. One of the assemblies inside the canister consistently experiences the least amount of turbulent flow and require the longest time to dry. Therefore, the assembly with the highest decay heat should be placed in this slot in the basket in order to facilitate the drying of this assembly. Conclusions The validated CFD model can be used in the future as a design and analysis tool for a full-scale drying setup with actual fuel assemblies.