bluuebunny/crossref_metadata_2025_split huggingface dataset:
Differential expression of PDL-1 and tumour-associated macrophages in N0 and N+ penile cancer.
Authors: Azhar Fowz , Sachdeva Ashwin , Hart Claire Alexandre , Brown Mick D. , Sangar Vijay , Parnham Arie , Lau Maurice , Oliveria Pedro , Clarke Noel W 
Published: March 2023

12 Background: Penile squamous cell carcinoma (PSCC) is rare, representing 0.4-0.6% of all male malignancies in the global-north, as compared with 2-10% in the global-south. Overall survival (OS) dramatically decreases with increased lymph node metastases (LNM). Increased prevalence of pro-tumorigenic M2 CD163+ tumour associated macrophages (TAM) is associated with poor PSCC OS, whereas increased prevalence of the generic M1/2 CD68+ TAMs is associated with better PSCC OS. PDL-1 expression has been noted in 40-60% of PSCC primary lesions. However, there is a paucity of evidence on the overall tumour immune microenvironment (TME) within penile LNM disease. This study describes the relationship between PDL-1 expression and TAMs within the TME of the primary tumour and paired LNMs, with the goal of predicting the utility of PD-1 inhibitors in clinical trials in PSCC. Methods: The Ventana Discovery ULTRA platform was used to optimise a 7-marker multiplex immunofluorescence panel on whole FFPE sections of primary and LNM lesions. Multispectral images were captured using a Vectra 3 microscope. Single cell spatial analysis was performed using HALO software, with statistical analysis of data using R 4.2.1. Results: 52 cases with differing LN stages were identified: N0 (N=20); N1/N2 (N=21); N3 (N=11). Increased expression of PDL-1 was noted at the primary lesion invasive margin (IM) of N+, compared with N0 patients. High expression in inguinal LNMs (iLN+) and pelvic LNMs (pLN+) was also observed, with no expression detected in microscopically normal, tumour free LNs (LN-) in the N0 cohort. More CD163+ M2 TAMs were observed at the IM of N+ compared with N0. However, no significant difference was observed between the three LN groups. M1/2 CD68+ TAMs were more prevalent within pLN+ vs iLN+ or LN-. There was no significant difference in M1/2 CD68+ TAMs number at the IM. Conclusions: Our data highlights increased prevalence of M2 CD163+ TAMs within the IM is associated with LNM. Increased presence of CD68+ M1/2 TAMs in pLN+ may represent active inflammation at the leading microscopic edge of metastatic deposits. A significant difference in the expression of PDL-1 between localised and metastatic disease at both primary and LN location is noted. High PDL-1 expression at the IM of the primary lesion is associated with increased LNMs, where PDL-1 expression is significantly higher as compared to LN-. This study supports the rationale for the use of anti-PD-1/PDL-1 therapies in patients with LNM disease.
Factors related to men’s experience with prostate cancer germline testing.
Authors: Giri Veda N. , Gross Laura , Hartman Rebecca , Leader Amy , Whang Young E. , Couvillon Anna , Cheng Heather H. , Paller Channing Judith , Loeb Stacy , Karsh Lawrence Ivan , Friedman Sue J. , Beer Tomasz M. , Sokolova Alexandra , Keith Scott W. 
Published: March 2023

128 Background: Indications for prostate cancer (PCA) germline testing (GT) have greatly expanded, with genetics delivery being implemented in a variety of ways. Here we evaluate factors related to men’s experience with genetic evaluation (GE) in the PCA Genetic Risk, Experience, and Support Study – PROGRESS Registry. Methods: Men took online surveys that covered demographics, PCA history, mode of GE, and measures of patient-reported outcomes (PROs) (satisfaction [Demarco 2004] [Score 6-30; higher=greater satisfaction], decisional conflict [O’Connor 1995] [Score 16-80; higher=greater conflict], attitude re: GT [Marteau 2001] [Score 1-7; higher=perceived benefit], and knowledge of cancer genetics [Erblich 2005] [% correct of 15 questions]). Data were summarized using descriptive statistics. Multiple linear regression modeling assessed relationships between characteristics, mode of GE, and PROs. Significance level was a nominal α = 0.05 (SAS v9.4). Results: PROGRESS reached accrual goal (n=500). Characteristics (among n=414): 87.7% White, 6.0% Asian, 87.7% bachelor’s degree or higher. Among n=422, 46.9% reported PCA diagnosis. Among n=416 who reported genetic results, 27.9% had pathogenic/likely pathogenic variants (P/LPV), 14.7% had VUS, and 9.9% did not know. Mode of GE was delivered: by genetics professional (GP) (24.9% in-person,10.5% phone, 6% telehealth), by doctor (21.1%), from website (20.8%), by genetics lab (5%), and by video (10.8%). Some reported not having pretest discussion (23.7%) or not knowing (8.1%). From multiple regression models, several factors including race, mode of GE, education, and genetic results were related to PROs. Conclusions: Several factors may impact men’s experience with PCA GE, deserving further study into root causes particularly related to diverse populations and genetics care delivery models to support men and their families. [Table: see text]
A retrospective review of the benefits vs. safety implications of prednisolone during docetaxel chemotherapy alongside androgen deprivation therapy (ADT) in metastatic hormone-sensitive prostate cancer (mHSPC).
Authors: Jameson Molly , Barker Claire , King Jennifer , Liang Hui-Wen , Carey Charles , Cripps Nicole , Jameson Daisy , Patel Kamlesh , Robinson Andrew , Hudson Andrew , Song Yee Pei , Conroy Ruth , Serra Maria , Choudhury Ananya , Logue John , Wylie James , Tran Anna 
Published: March 2023

132 Background: A key difference between the landmark trials for docetaxel chemotherapy alongside ADT for mHSPC was the addition of prednisolone in the STAMPEDE but not CHAARTED or GETUG-AFU 15 trials, resulting in varied use in clinical practice. Potential toxicity from prolonged steroid use was recognised in a 2020 NHS England safety alert. This retrospective study compared toxicities in patients treated with docetaxel +/- prednisolone. Methods: Electronic notes of patients treated with docetaxel and ADT +/- prednisolone (per consultant preference) Feb 2018 - Sept 2020, were reviewed. Data was collected on common toxicities using CTCAE v5 grading. Analysis of incidence and severity were carried out using paired T-tests and logistic regression due to small sample sizes at each severity grade. Results: Data on 299 patients was collected; 167 received docetaxel and ADT, 132 also received prednisolone. There was no significant difference in the number of cycles completed between the 2 groups; 66.5% (no prednisolone) v 70.4% (with prednisolone) of patients completed 6 cycles (p=0.41). There was a significant difference in both the incidence and severity of anaemia between patients treated +/- prednisolone. There was no significant difference in the incidence of neutropenia or alopecia between patients treated +/- prednisolone, but prednisolone use was predictive of lower severity scores in neutropenia and alopecia. In contrast, there was a significant difference seen in incidence of neuropathy between the 2 groups, with no impact on severity. There was no significant difference in incidence or severity of thrombocytopenia, neutropenic sepsis, fatigue or nausea/vomiting. The prednisolone group had a significant increase in contacts with an advice hotline or general practitioner (p values <0.001). Review of interactions found many were requesting support with administration of prednisolone. Conclusions: These findings suggest limited clinical benefit in the addition of prednisolone to docetaxel and ADT in patients with mHSPC. Prednisolone is associated with significant potential harms e.g., impaired blood glucose and adrenal insufficiency (blood glucose was not routinely recorded in this group). These preliminary findings would benefit from further study with a larger sample size. [Table: see text]
COVID-19 vaccination behavior and outcomes in patients with genitourinary cancer in comparison with other cancer types.
Authors: Polimera Hyma Vani , Pomerantz Lauren Danielle , Guare Emma , Zhu Junjia , Joshi Monika 
Published: March 2023

134 Background: Cancer(ca) and old age are risk factors for developing severe COVID-19 (C19+) disease, related morbidity and mortality. These patients (pts) were excluded from clinical trials evaluating the safety and efficacy of 3 FDA approved C19 vaccines (vax). Genitourinary (GU) ca-prostate, bladder and kidney ca contribute to the majority of non-skin ca and median age of these pts range from 65-75 yrs. We aimed to study these highly vulnerable pts behavior and outcomes regarding C19 vax in comparison to non-GU ca pts (18-89 years). Methods: A prospective and observational single center study. Adult ca pts seen in clinics from Nov 2021-Sept 2022 were randomly interviewed using telephone surveys after a verbal consent. Type of ca and therapy data were collected from pts’ medical records. The survey included C19 disease status, vax status positive (+) or negative (-), reason for vax status, side effects (s.e), impact on ca Rx or ca progression. Data was entered on REDCap. The primary end point was rate of vaccination in adult ca pts. Secondary end points were to quantify C19 vax acceptance vs. hesitance, identify s.e of C19 vax and effect of C19 vax on outcomes in GU and non-GU Ca pts. Results: N=172; GU ca 21 (12.2%) and non-GU ca 151 (87.8%). Among GU ca pts- 9 had prostate ca, 7 had bladder ca and 5 had renal ca. C19+ in 4 (19%) GU and 45 (30.2%) non-GU pts. GU pts: 90.5% received C19 vax (Pfizer 47.6%; Moderna 42.9%, J & J 0%); 9.5% were not vaxed. Non-GU pts: 85.2% received C19 vax (Pfizer 39.1%; Moderna 43%, J & J 2.6%); 14.8% were not vaxed. The top 3 risk factors for serious C19+ were age >65yr (76.2%), heart disease (61.9%) and BMI>30 (42.9%) in GU ca pts and age >65yr (46.4%), BMI>30 (35.1%) and smoking (19.9%) in non-GU ca pts. The top 3 reasons for C19 vax (+) in GU ca pts: protection against C19+ for self (81%), for others (47.6%) and provider recommendation (38.1%). The main reasons for vax hesitancy in C19 vax (-) GU ca pts: concern for allergy to the vax (4.8%) and prior C19 infection (4.8%). The common s.e of C19 vax reported in GU ca pts were injection site inflammation (19%), headache (4.8%), muscle/body aches (4.8%) but no lymphadenopathy. None of GU ca pts reported delay in Rx or progression of the disease due to C-19 vax. Conclusions: C19 vax were overall well tolerated and did not impact ca outcomes in pts with GU malignancies. Oncologists should discuss the importance of C19 vax in the context of ca. Clinical trial information: NCT04953065 . [Table: see text]
Dosing, safety, and pharmacokinetics (PK) of combination therapy with darolutamide (DARO), androgen-deprivation therapy (ADT), and docetaxel (DOC) in patients with metastatic hormone-sensitive prostate cancer (mHSPC) in the ARASENS study.
Authors: Rezazadeh Arash , Tombal Bertrand F. , Hussain Maha H. A. , Saad Fred , Fizazi Karim , Sternberg Cora N. , Crawford E. David , Kapur Shivani , Zhang Weijiang , Ploeger Bart , Li Rui , Kuss Iris , Zieschang Carsten , Wittemer-Rump Sabine , Smith Matthew Raymond 
Published: March 2023

148 Background: In ARASENS (NCT02799602), DARO in combination with ADT and DOC significantly reduced the risk of death by 32.5% (HR 0.68; 95% CI 0.57–0.80; P<0.001) vs placebo (PBO) + ADT + DOC in patients with mHSPC. Incidences of treatment-emergent adverse events (TEAEs) were similar between treatment groups. We report dosing, safety, and PK of coadministration of DARO and DOC with ADT. Methods: Patients with mHSPC were randomized 1:1 to DARO 600 mg twice daily or PBO, plus ADT and DOC (75 mg/m2 q21d for 6 cycles). The effect of DARO on DOC PK was assessed by noncompartmental analysis from the first 25 patients with dense PK data and by population PK (PopPK) for all patients. DARO PK from ARASENS were compared with PK data from ARAMIS (NCT02200614; without DOC) to evaluate the impact of DOC on DARO PK. Results: Of 1306 randomized patients, 1305 were included in the full analysis set (DARO, n=651; PBO, n=654). The median treatment duration was longer with DARO vs PBO (41.0 vs 16.7 months) and more DARO-treated patients (45.9% vs 19.1%) were still receiving treatment at primary analysis cutoff (Oct 25, 2021). Almost all patients completed 6 cycles of DOC in both groups (DARO, 87.6%; PBO, 85.5%). The proportion of patients requiring DOC dose modification (interrupted/delayed or reduced) was similar between groups (DARO, 60.0%; PBO, 62.9%). TEAEs led to discontinuation/reduction of DOC in 8.0%/19.9% of DARO patients and 10.3%/19.5% of PBO patients. PopPK analysis indicated that DOC PK in ARASENS was generally consistent with that in the literature. A slight numeric increase in DOC exposure was observed in the DARO + DOC + ADT arm, with 15% higher maximum plasma concentration (geometric mean, 1.93 vs 1.68 µg/mL) and 6% higher area under the concentration-time curve (AUC0-tlast within an 8-hour sampling interval, 2.10 vs 1.99 µg·h/mL) vs PBO + DOC + ADT. This small numeric increase is likely not clinically relevant given the variability in DOC exposure (coefficient of variation, 23%–54%). PK meta-analysis of ARASENS and, which considered patients’ intrinsic characteristics as covariates (eg, age, body weight, region), indicated a 10% lower AUC0-12ss of DARO in patients receiving DOC vs those not receiving DOC, which is not considered clinically relevant. Conclusions: The combination of DARO + DOC + ADT increases overall survival with similar overall incidence of TEAEs and no observed drug-drug interactions between DARO and DOC. DARO can be effectively and safely administered with DOC in patients with mHSPC without clinically relevant changes in PK of DARO or DOC. Clinical trial information: NCT02799602 .
Therapeutic effect of gedatolisib, a pan-PI3K/mTOR inhibitor, on prostate cancer models with PI3K or PTEN mutational status.
Authors: Sen Adrish , Khan Salmaan A , MacNeil Ian A. , Rich Benjamin E. , Molden Jhomary S , Davis Laura N , Rossetti Stefano , Broege Aaron M , Laing Lance G. 
Published: March 2023

149 Background: Metastatic castration-resistant prostate cancer (mCRPrC) is characterized by a loss of androgen receptor (AR) sensitivity and oncogenic activation of the PI3K, AKT, and mTOR (PAM) pathway. Loss of the PI3K regulator, PTEN, is frequent during prostate cancer (PrC) initiation, progression, and therapeutic resistance. Co-targeting PAM/AR pathways is a promising PrC treatment strategy but hampered by complex PAM-AR pathway crosstalk driving either reciprocal negative feedback inhibition or feedback relief. Most PAM inhibitors (PAM-i) selectively spare (or weakly inhibit) one or more key PAM pathway components, potentiating drug resistance depending on the PAM mutation status of patients. AKT-i demonstrated limited efficacy in PTEN-deficient PrC and even less efficacy in PTEN-wild type (wt) in recent clinical studies, suggesting that more comprehensive inhibition of the PI3K isoforms and mTOR may be required. We posited that gedatolisib, a well-tolerated and potent inhibitor of all Class I PI3K isoforms, mTORC1, and mTORC2, would be effective in both PTEN-wt and PTEN-deficient PrC. Methods: A panel of PrC cell lines with different PI3K or PTEN status ( wt: 22RV1, MDA-PCa-2b, DU145; null: LNCaP, PC3, C4-2) were assayed under different conditions for their sensitivity to gedatolisib and other PAM-I ( PI3K: alpelisib, copanlisib; AKT: capivasertib, ipatasertib; mTOR: everolimus; pan-PI3K/mTOR: samotolisib, gedatolisib). A combination of cell viability, growth rate, cytotoxicity and phospho-FACS analytical assays were used. Xenograft studies evaluating gedatolisib with a subset of these models were also performed in castrated mice. Results: We confirmed that AKT-i is more effective in PTEN-null than PTEN-wt PrC. In contrast, the two pan-PI3K/mTOR-i evaluated were effective independent of PI3K or PTEN status. Gedatolisib exhibited superior potency and efficacy compared to each of the other PAM-i for cell proliferation, death, or PAM pathway activation. In vivo, gedatolisib substantively inhibited tumor growth regardless of PTEN or PI3K status. Conclusions: We demonstrated that gedatolisib exerts superior activity regardless of PI3K or PTEN status in all PrC cell lines evaluated compared to the other PAM pathway inhibitors evaluated. Our results indicate potent and simultaneous blockade of all Class I PI3K isoforms, mTORC1, and mTORC2 could circumvent PTEN dependent resistance. Gedatolisib as a single agent and in combination with other therapies reported promising preliminary efficacy and safety in various solid tumor types. In light of the PrC findings reported here, development of gedatolisib may be warranted in PrC patients regardless of their PTEN or PI3K status.
Efficacy and safety of darolutamide (DARO) in combination with androgen-deprivation therapy (ADT) and docetaxel (DOC) by disease volume and disease risk in the phase 3 ARASENS study.
Authors: Hussain Maha H. A. , Tombal Bertrand F. , Saad Fred , Fizazi Karim , Sternberg Cora N. , Crawford E. David , Shore Neal D. , Kopyltsov Evgeny , Rezazadeh Arash , Boegemann Martin , Ye Ding-Wei , Cruz Felipe Melo , Suzuki Hiroyoshi , Kapur Shivani , Srinivasan Shankar , Verholen Frank , Kuss Iris , Joensuu Heikki , Smith Matthew Raymond 
Published: March 2023

15 Background: In ARASENS (NCT02799602), DARO plus ADT and DOC significantly reduced the risk of death by 32.5% (HR 0.68; 95% CI: 0.57–0.80; P<0.0001) vs placebo (PBO) + ADT + DOC in patients (pts) with metastatic hormone-sensitive prostate cancer (mHSPC), with similar overall incidences of treatment-emergent adverse events (TEAEs) between groups. The effect of DARO on overall survival (OS) was consistent across prespecified subgroups, including de novo and recurrent disease. For pts with mHSPC, outcomes based on disease volume and risk provide additional information to clinicians. Methods: Pts with mHSPC were randomized 1:1 to DARO 600 mg twice daily or PBO, with ADT + DOC. High-volume disease was defined as visceral metastases and/or ≥4 bone metastases with ≥1 beyond the vertebral column/pelvis (CHAARTED criteria). High-risk disease was defined as ≥2 risk factors: Gleason score ≥8, ≥3 bone lesions, and presence of measurable visceral metastasis (LATITUDE criteria). OS for these subgroups was assessed using an unstratified Cox regression model. Results: Of 1305 pts in the full analysis set, 1005 (77%) had high-volume disease, 912 (70%) had high-risk disease, 300 (23%) had low-volume disease, and 393 (30%) had low-risk disease. DARO + ADT + DOC prolonged OS regardless of high- or low-volume disease with HRs of 0.69 and 0.68 vs PBO + DOC + ADT, respectively. OS benefit of DARO vs PBO was also similar for pts with high- or low-risk disease. DARO improved clinically relevant secondary endpoints vs PBO in high/low-volume and risk subgroups, with HRs generally in the range of those observed in the overall population. Incidences of TEAEs were consistent with the overall ARASENS population across subgroups by high/low volume and high/low risk. Conclusions: In pts with mHSPC, the benefits of early treatment intensification with DARO + ADT + DOC on OS and key pt-relevant secondary efficacy endpoints vs PBO + ADT + DOC were similar in patients with high- and low-volume as well as high- and low-risk mH+SPC. The favorable safety profile of DARO was reconfirmed in high/low-volume and high/low-risk populations. DARO + ADT + DOC sets a new standard of care for pts with mHSPC. Clinical trial information: NCT02799602 . [Table: see text]
The effect of reduced dose of apalutamide on skin adverse events in advanced prostate cancer: A multicenter retrospective study.
Authors: Hatakeyama Shingo , Tabata Ryuji , Fujita Naoki , Tanaka Toshikazu , Yoneyama Takahiro , Sato Satoshi , Ohyama Chikara 
Published: March 2023

151 Background: We aimed to evaluate the effect of a reduced dose of apalutamide on skin-related adverse events (AEs) and castration-sensitive prostate cancer (CRPC)-free survival in patients with advanced prostate cancer. Methods: We retrospectively evaluated 35 patients with non-metastatic CRPC and 72 treatment naïve metastatic castration-sensitive prostate cancer (mCSPC) who were treated with apalutamide. The primary outcome was the effect of apalutamide dose-reduction on skin AEs. The secondary outcomes included the effect of apalutamide dose-reduction on skin AE in patents with small body size, post-skin AEs discontinuation rate, and the effect of apalutamide dose-reduction on CRPC-free survival in patients with mCSPC treated with upfront apalutamide plus androgen deprivation therapy. Results: Of 107 patients, 65 (60.7%) and 42 (39.3%) patients were treated with full- and reduced-dose of apalutamide, respectively. The skin AEs rate was not significantly different between the groups (55% vs. 43%, P = 0.761). The incident of skin AEs in the reduced dose of apalutamide were significantly lower in patients with small body size (body weight <67kg and body mass index < 24kg/m2) than those in other body sizes. Apalutamide discontinuation rate after skin AEs was significantly different between the full-dose (50%) and reduced-dose (16.7%) groups. Of 72 patients with mCSPC, the CRPC-free survival was not significantly different between the full- and reduced-dose groups. Conclusions: A reduced dose of apalutamide was not significantly associated with the incident of skin AEs. However, dose reduction for patients with small body size may decrease skin AEs without sacrificing oncological outcome.