bluuebunny/crossref_metadata_2025 huggingface dataset:
Cancer-control outcomes of metastatic castration resistant prostate cancer patients with
BRCA
-gene or tumor suppressor mutations undergoing 177-lutetium PSMA radioligand therapy.
Authors: Wenzel Mike , Koll Florestan , Hoeh Benedikt , Humke Clara , Reis Henning , Wild Peter , Steuber Thomas , Graefen Markus , Tilki Derya , Sabet Amir , Groener Daniel , Chun Felix , Mandel Philipp
Published: February 2025

71

Background:
Several tumor gene mutations are known for metastatic castration-resistant prostate cancer (mCRPC) are known. The individual response to 177-Lutetium Prostate-specific membrane antigen (Lu-PSMA) therapy is under current investigation regarding the genomic profile of mCRPC patients.
Methods:
We relied on the FRAMCAP database and compared progression-free (PFS) and overall survival (OS) rates of mCRPC patients with Breast Cancer related antigen (
BRCA
) or tumor suppressor gene mutations (
TP53, PTEN, RB1
[TSG]). Especially, subgroup analyses were performed for Lu-PSMA-treated mCRPC patients.
Results:
Of 194 mCRPC patients, 22% were
BRCA1/2
vs. 14% TSG vs. 63% without one of these mutations. Patients with no mutation harbored significantly lower Gleason score 8-10, relative to
BRCA
and TSG patients. In PFS analyses of first line mCRPC, no difference between all three groups was observed, while median OS differed significantly with 46.3 vs. 48.7 vs. 95.4 months for
BRCA
vs. TSG vs. no mutated patients (p<0.05). In univariable Cox regression models, BRCA mutated patients were at higher risk for death (hazard ratio [HR]: 2.57, p<0.01), while TSG patients were not (p=0.4). Of 87 Lu-PSMA treated mCRPC patients, significant differences in PFS and OS were made (both p≤0.02). In univariable and multivariable Cox regression models, BRCA mutated Lu-PSMA patients were at higher risk for death, while
TSG
patients had similar outcomes as no mutated patients.
Conclusions:
In real-world setting, substantially lower OS in mCRPC is observed for
BRCA
and TSG mutated patients, while no difference in first line PFS could be computed. In Lu-PSMA-treated patients, worst outcomes were observed for
BRCA
patients.

Age at mCRPC, years
149
68 (61, 75)
66 (61, 71)
69 (65, 80)
69 (63, 76)
0.3

PSA at CRPC, ng/ml
105
12 (3, 50)
12 (1, 72)
5 (3, 36)
13 (4, 46)
0.8

Treatment lines mCRPC
194
3.00 (1.00, 4.00)
3.00 (1.00, 4.50)
3.00 (1.00, 4.00)
3.00 (1.00, 4.00)
0.6

ECOG status at mCRPC
79

0.017

0

47 (59%)
7 (44%)
12 (92%)
28 (56%)

1

32 (41%)
9 (56%)
1 (7.7%)
22 (44%)

≥2

0 (0%)
0 (0%)
0 (0%)
0 (0%)

Cardiovascular disease
168
52 (31%)
9 (23%)
6 (21%)
37 (37%)
0.15

Gleason Score
179

0.032

8-10

130 (73%)
34 (83%)
22 (81%)
74 (67%)

De Novo mHSPC
186
123 (66%)
32 (76%)
18 (64%)
73 (63%)
0.3

High volume mHSPC
126
73 (58%)
24 (71%)
12 (63%)
37 (51%)
0.13

Metastatic sites at mCRPC
92

0.2

M1a

6 (6.5%)
1 (4.5%)
2 (10%)
3 (6.0%)

M1b

75 (82%)
15 (68%)
17 (85%)
43 (86%)

M1c

11 (12%)
6 (27%)
1 (5.0%)
4 (8.0%)

PARPi Treatment
194
25 (13%)
15 (35%)
1 (3.6%)
9 (7.3%)
<0.01

1
Median (IQR); n (%).

2
Kruskal-Wallis rank sum test; Fisher’s exact test; Pearson’s Chi-square test.
Bayesian re-analysis: Comparing radical cystectomy with trimodality therapy in patients with muscle invasive bladder cancer.
Authors: Pepin Abigail , Mamtani Ronac , Christodouleas John Paul , Lee Daniel
Published: February 2025

737

Background:
Randomized trials comparing radical cystectomy (RC) and trimodality therapy (TMT) in muscle invasive bladder cancer (MIBC) have not been feasible. In 2023, Zlotta et al. published a retrospective multi-institutional analysis evaluating metastasis free survival (MFS) and overall survival (OS) outcomes in patients treated with RC or TMT. Zlotta et al. is generally considered the highest quality data available for this comparison, but the results were presented using traditional frequentist statistics which can be challenging to interpret. The purpose of this study was to use Bayesian re-analysis of Zlotta et al. to convert its frequentist summary statistics into outcome probabilities, enabling a more intuitive treatment comparison between RC and TMT.
Methods:
The Zlotta et al. study results comparing RC and TMT were described by estimating the probability of any benefit (HR<1) or a minimal clinically meaningful (MCR) benefit (HR<0.8). An informative neutral prior distribution was defined by surveying bladder cancer experts on the comparison of RC and TMT use in bladder cancer patients included in Zlotta et al. (cT2–T4N0M0, <7cm, no or unilateral hydronephrosis, no CIS, average age 70). Using a neutral prior of no advantage to either treatment and methods adapted from Wijeysundera et al., we calculated probabilities of a benefit in MFS and OS. We performed sensitivity analyses by varying the strength of the study-specific priors’ neutrality assumption and by using an alternative informative neutral prior developed for oncology comparisons but not specifically for MIBC.
Results:
The expert-informed informative neutral prior assumption assumed a 70% chance that any differences with respect to any cancer control or overall survival outcome would be less than the minimal clinically significant thresholds. The posterior probabilities of the primary analysis are presented in the table. Sensitivity analyses of the estimates of any benefit for MFS and OS varied by up to 3%, while estimates of a MCR benefit for MFS and OS varied up to 15%.
Conclusions:
The best available evidence suggests that in selected MIBC patients there is a >96% chance that TMT is associated with any OS advantage over RC but a <59% chance that the benefit reaches a minimal clinically meaningful benefit threshold. There is >65% chance that TMT is associated with any MFS advantage over RC but <13% chance of a minimal clinically meaningful benefit.

Bayesian re-analysis of outcome estimate from Zlotta et al. 2023.

Probability of any benefit of TMT over RC (HR<1)
Probability of any benefit of RC over TMT (HR>1)
Probability of a MCR benefit of TMT over RC (HR<0.8)

Adjusted MFS

Zlotta et al. Outcomes

IPTS
SHR 0.89 (95% CI 0·67–1·20)
73%
27%
12%

PSM
SHR 0.93 (95% CI 0.71–1.24)
66%
34%
7%

Adjusted OS

IPTS
SHR 0.70(95% CI 0.53–0.92)
98%
2%
58%

PSM
SHR 0.75 (95% CI 0.58–0.97)
97%
3%
44%
Evaluating the survival benefits of adjuvant immunotherapy in muscle-invasive urothelial carcinoma: A real-world experience.
Authors: Zahir Mazyar , Doshi Chirag , Escobar Domenique , Xia Leilei , Miranda Gus , Cai Jie , Schuckman Anne K. , Djaladat Hooman , Daneshmand Siamak
Published: February 2025

750

Background:
Despite current guidelines recommendations to administer adjuvant nivolumab following radical cystectomy (RC) in patients with adverse pathologies, regardless of prior neoadjuvant chemotherapy (NAC), evidence on the long-term efficacy of ICIs remains sparse. This study aims to evaluate the potential survival benefits of the two most common ICIs, Nivolumab and Pembrolizumab, in patients with muscle-invasive bladder cancer (MIBC) at a single institution.
Methods:
We queried our IRB-approved, prospectively maintained institutional RC database for all patients who underwent RC from January 2017 (following FDA approval for ICIs in MIBC) to July 2022. Patients with pT3-4a and/or N+ after RC, or ypT2-4a and/or N+ after NAC + RC, were included and categorized into two groups: those who received adjuvant ICI (ICI+) and those who did not (ICI-). Demographic, clinical, and survival data were retrieved from our database. Multivariable Cox regressions were performed to adjust for potential confounding variables.
Results:
A total of 191 patients were included, with 38 (19.9%) receiving adjuvant ICI (30 Nivolumab and 8 Pembrolizumab). The table outlines the patient characteristics, stratified by adjuvant ICI treatment. With a median follow up of 17.9 months, overall survival (OS) was 97.4% in the ICI+ group and 66.0% in the ICI- group (p = .003). Recurrence-free survival (RFS) was 84.2% and 67.9% in the ICI+ and ICI- groups, respectively (p=.206). in the ICI- group, 10 out of 49 (20.4%) recurrences were local or regional (i.e. urethral or ureteral), while all recurrences (N=6) in the ICI+ group were distant. Multivariable Cox regressions demonstrated that, after adjusting for age and pathological stage, adjuvant ICI was associated with significantly improved OS (HR = 0.08 [95%CI: 0.01, 0.59], p = .013), but not RFS (HR = 0.43 [95%CI: 0.18, 1.04], p = .062).
Conclusions:
Our results corroborated the beneficial effect of ICIs on OS. Although the improvement in RFS did not reach statistical significance, ICIs showed a trend toward positive clinical impact. A notable finding was the potential for ICIs to alter the recurrence pattern in MIBC. Although limited by a small sample size, this study represents one of the first real-world evaluations of adjuvant ICI efficacy in a single-institution cohort.

Demographics and baseline clinical characteristics.

ICI+ (N=38)
ICI- (N=153)

p

Age (years)
68.7 ± 8.6
71.6 ± 10.4
.060

Sex (Male)
27 (71.1%)
118 (77.1%)
.433

Charleson Comorbidity Index
0
9 (23.7%)
31 (20.3%)
.886

1
6 (15.8%)
27 (17.6%)

≥ 2
23 (60.5%)
95 (62.1%)

Pathological staging
OC (< (y)pT2; pN0)
3 (7.9%)
29 (19.0%)
.013

EV (> (y)pT2; pN0)
11 (28.9%)
67 (43.8%)

LN+ (pN+)
24 (63.2%)
57 (37.2%)

Neoadjuvant Chemotherapy (yes)
30 (79.0%)
85 (55.6%)
.008
Patient and caregiver preferences for the treatment of locally advanced or metastatic urothelial carcinoma (la/mUC): Results of a targeted literature review (TLR).
Authors: Kearney Mairead , Janssens Rosanne , Quaife Matt , Trapali Myrto , Thomas Caitlin
Published: February 2025

755

Background:
The treatment landscape for la/mUC has evolved with multiple care options available. As new therapies are adopted, decision-making among physicians, patients, and their caregivers becomes more complex and challenging. This study summarizes the existing literature on preferences of patients and caregivers about aspects of treatment following a diagnosis of la/mUC.
Methods:
A TLR of English-language conference abstracts and full-text manuscripts published from 2015 was conducted using Embase and PubMed, to identify qualitative and quantitative studies on the treatment preferences of patients with la/mUC and caregivers of people with la/mUC. Literature was independently screened against predefined eligibility criteria by two researchers, with a third researcher resolving disagreements.
Results:
Data from 13 publications were extracted (n=10 [77%] qualitative, n=3 [23%] quantitative); of these, 6 (46%) were full-text manuscripts and 7 (54%) were conference abstracts/posters. When specified, most studies (6/10 [60%]) were conducted in the US. Six studies (46%) assessed preferences among both patients and caregivers. The quantitative preference studies assessed varied efficacy endpoints, including overall survival (n=2), overall response rate (ORR; n=1), and progression-free survival (n=1). Treatment efficacy was the most important consideration in 2 quantitative studies, while 1 study found adverse events (AEs), combined with number and duration of medicines, to be more important to patients. Across publications, attributes related to treatment AEs significantly impacted preferences. Unmet needs related to symptoms and AEs were identified. The symptoms/AEs reported most frequently across all 13 studies were fatigue (n=7 [53%]), cancer-related pain (n=6 [46%]), peripheral neuropathy (PN; n=3 [23%]), blood in urine (n=3 [23%]), and nausea (n=3 [23%]). In 1 quantitative study, cancer-related pain was ranked as the second most important treatment attribute after ORR. Patients in this study also indicated that they would accept a 7.8% reduction in ORR to reduce the risk of developing PN by 10%. Of 3 studies that compared differences between patient and caregiver preferences, 2 quantitative studies found that caregivers placed a higher importance on avoiding side effects than patients.
Conclusions:
Despite heterogeneity in study designs and outcomes reported, patients and caregivers often prioritized treatment efficacy over tolerability. However, in quantitative studies, patients and caregivers were willing to accept lower efficacy for a more tolerable treatment, although the magnitude of trade-offs varied by AE. Such insights highlight the importance of incorporating patient and caregiver preferences in shared decision-making and personalizing treatment according to individual patient goals.
Influence of gut microbiome composition on treatment efficacy and toxicity in bladder cancer: A comprehensive meta-analysis.
Authors: Sarwar Atif Hussain , Hashim Hashim Talib , Alhatemi Ahmed Qasim Mohammed , Saddique Muhammad Nabeel , Shamoon Sheena
Published: February 2025

768

Background:
The gut microbiome has emerged as a critical factor influencing the efficacy and toxicity of cancer treatments. In bladder cancer, variations in microbiome composition may affect patient responses to therapy, including immunotherapy and chemotherapy. This meta-analysis aims to comprehensively evaluate the impact of gut microbiome composition on treatment outcomes in bladder cancer.
Methods:
The PubMed, Embase, Scopus and Cochrane databases were systematically searched from inception until June 2024 using relevant keywords. The pooled data were presented as Odds Ratio (OR) with 95% confidence intervals (CI) using Random Effects model in OpenMeta (version 5.3). The I
2
and X
2
statistics were used to evaluate inter-study heterogeneity. An I
2
value of >50% was considered significant heterogeneity. The subgroup analyses were conducted to identify specific microbiome profiles associated with different treatment responses.
Results:
A total of 20 studies comprising 2,500 bladder cancer patients were included in the meta-analysis. Patients with a higher abundance of beneficial bacteria such as
Bifidobacterium
and
Lactobacillus
had significantly better treatment responses (OR: 2.5, 95% CI: 1.8-3.4) and lower toxicity rates (OR: 0.6, 95% CI: 0.4-0.9). Conversely, an increased presence of pathogenic bacteria like
Clostridium
and
Escherichia coli
was associated with poorer outcomes (OR: 0.5, 95% CI: 0.3-0.8) and higher toxicity (OR: 1.9, 95% CI: 1.3-2.7).
Conclusions:
This meta-analysis highlights the significant influence of gut microbiome composition on the efficacy and toxicity of bladder cancer treatments. Identifying specific bacterial profiles associated with positive and negative outcomes could guide personalized treatment strategies and improve patient care. Further research is needed to understand the mechanisms underlying these associations and to develop microbiome-targeted therapies.
Second-line platinum-based chemotherapy (PBT) in patients with metastatic urothelial carcinoma (mUC) treated with first-line pembrolizumab plus enfortumab vedotin (P/EV): A single-center, retrospective study.
Authors: Kim Junkyu , Park Se Hoon , Kim Changgon , Hyeon Jiyeon , Lim Sung Hee , Kwon Minsuk
Published: February 2025

785

Background:
Although the efficacy of PBT as first-line therapy for mUC has been known for more than 30 years, the recent integration of P/EV as a preferred first-line option prevented the use of evidence-based regimen. Since the available second-line regimens depend on what was given as first-line, we evaluate the efficacy and tolerability of second-line PBT in mUC patients treated with first-line P/EV.
Methods:
We retrospectively reviewed the medical records of 37 patients with mUC who were treated with first-line P/EV, mostly in clinical trials, between Jan 2022 and Jan 2024 at Samsung Medical Center (Seoul, Korea). Patients with mUC whose disease progressed during or after first-line treatment with P/EV received PBT involving gemcitabine plus either cisplatin or carboplatin (determined on the basis of cisplatin-eligibility). Primary endpoints included safety and response rates.
Results:
Among a total of 37 first-line P/EV patients, 10 received second-line PBT: gemcitabine plus cisplatin (n = 8) and plus carboplatin (n = 2). The median age was 68 years (range, 48 to 82 years) and the median interval from the last dose of P/EV was 50 days (range, 15 to 89 days). A total of 33 PBT cycles were given (median, 2; range 1 to 6). One patient achieved a complete response and 3 had a stable disease. Although peripheral neuropathy and gastrointestinal toxicities were the most frequently encountered adverse events, safety profile was generally manageable. Median progression-free and overall survivals were 3.4 months (95% CI, 2.3 to 4.5) and 8.0 months (95% CI, 6.1 to 19.9), respectively.
Conclusions:
Second-line PBT for mUC patients treated with first-line P/EV does not appear highly active but the observation of responders merits further studies in those with medically-fit, platinum-eligible patients.
A phase 2 study of cabozantinib in combination with atezolizumab as neoadjuvant treatment for muscle-invasive bladder cancer, (HCRN GU18-343) ABATE study.
Authors: Kilari Deepak , Szabo Aniko , Bylow Kathryn , Nelson Ariel Ann , Langenstroer Peter , Johnson Scott , Sivaraman Arjun , Jacobsohn Kenneth , Fung Chunkit , Kadambi Sindhuja G , Rini Brian I. , Reimers Melissa A , Alter Robert S. , Paul Asit KR , Guercio Brendan John , Milowsky Matthew I.
Published: February 2025

800

Background:
Atezolizumab (A) has demonstrated single agent activity as neoadjuvant therapy (NAT) for muscle invasive urothelial carcinoma (MIUC) (ABACUS trial). Cabozantinib (C) has a unique immunomodulatory profile that may foster anti-tumor immunity and has demonstrated clinical activity as monotherapy and in combination with A. We hypothesized that the combination of C and A as NAT for MIUC would improve pathologic response rate (pRR) compared to single-agent A.
Methods:
This open-label, single arm, multi-center study investigated the efficacy and safety of C 40 mg PO daily with A 1200mg every 3 weeks for 9 weeks as NAT for cT2-T4aN0/xM0 MIUC. Eligibility required patients (pts) to be cisplatin-ineligible or decline cisplatin, with UC as the predominant histology (≥ 50%). Primary endpoint was pRR defined as no residual muscle-invasive cancer in the surgical specimen (< ypT2); patients with progression prior to cystectomy were counted as non-responders. pRR was to be compared to the 39% response rate with the single agent A using a Bayesian evaluation with a Beta (0.5, 0.5) prior. Secondary endpoints were safety and toxicity, pathologic complete response rate (pCR, ypT0N0M0) and event-free survival (EFS). Exploratory end points included patient-reported outcomes and outcome associations with biomarkers.
Results:
From Feb 2021 to July 2024, 46 pts enrolled at 5 sites. 2 pts were deemed ineligible, and 6 pts did not proceed with cystectomy for reasons other than progression (4 pts opted for bladder preservation, 1 pt died from causes unrelated to tx and 1 pt still undergoing tx). Median follow up is 14 mo. At study entry median age was 71 yrs, 21% were female, 98% Caucasian and 71% were cisplatin ineligible, with T2, T3 and T4 disease in 73%, 18% and 9% respectively. Histology included pure urothelial cancer (56%), squamous (18%), glandular (3%), micropapillary (18%) and plasmacytoid (5%) differentiation. Among 35 pts who underwent cystectomy, 32 (91%) / 3 (9%) completed 3 and 2 doses of A and 15 (43%) / 32 (91%) completed 9 and at least 6 weeks of C. Adverse events are being analyzed. The estimated pRR was 29.5% (95% CrI 16.5% - 44.5%) and the pCR was 20.8% (95% CrI 9.4% - 35.3%). The pCR was lower in pts with variant histology compared to pure UC (13 vs 25%; p=0.39). 2-year EFS was 68.4% (95% CI, 47.7-82.3%).
Conclusions:
C+A has modest activity as NAT in MIUC and did not meet the pre-specified primary endpoint for pRR. Biomarkers studies are planned. Clinical trial information:
NCT04289779
.
A heterologous prime-boost strategy using RUTI vaccine to improve the BCG response in non–muscle-invasive bladder cancer patients (RUTIVAC-1 trial).
Authors: Buisan Oscar , Servian Pol , Pedreño-Lopez Sonia , Pagès Joan , Urrea Victor , Martinez Roberto , Garcia Elisabet , Amat Mercè , Areal Joan , Bellmunt Joaquim , Clotet Bonaventura , Cabrera Cecilia
Published: February 2025

801

Background:
Despite standard-of-care therapy with transurethral resection of bladder tumor and intravesical BCG instillation, a significant percentage of patients with non-muscle invasive bladder cancer (NMIBC) experience disease recurrence or progression. Therefore, novel combination therapies are needed to improve BCG efficacy. The RUTIVAC-1 trial, a randomized, double-blind, placebo-controlled, phase I study, was conducted to investigate the potential of a heterologous prime-boost strategy using RUTI, a nonlive vaccine composed of
Mycobacterium tuberculosis
cell wall fragments, as a primer to enhance the intravesical BCG-induced immune response in NMIBC patients.
Methods:
Forty high-grade, BCG-naïve NMIBC patients were randomized 1:1 to receive two subcutaneous doses of either placebo or RUTI (25 μg)

before standard BCG treatment. The primary endpoint was the immunological changes after RUTI vaccination. Secondary endpoints included clinical efficacy (recurrence, progression and mortality rates) and safety at 5-year follow-up.
Results:
Baseline characteristics were similar in both groups (median age 70 years, 90% male, 65% T1, 32.5% Ta and 4% CIS). RUTI vaccination induced a vaccine-specific CD4
+
and CD8
+
T cell response prior to the initiation of intravesical BCG therapy. Following intravesical BCG treatment, the placebo group showed an increase in regulatory T cells (Tregs; CD4
+
CD25
+
CD27
+
), which was not observed in the RUTI group. Conversely, RUTI-vaccinated patients exhibited a more heterogeneous and polyfunctional specific immune response, with significant increases in PPD-specific CD25
+
, CD137
+
, OX40
+
and CD69
+
CD4
+
T cells, as well as bi- and trifunctional CD4
+
T cells expressing IFN-γ, TNF-α, and IL-2. Efficacy after 5 years of follow-up correlated with immunological changes, with RUTI vaccination associated with a significant increase in progression-free survival (100% vs. 72.2%; p=0.015), an 80% reduction in the risk of experiencing an event (EFS 89.5% vs. 50%; HR: 0.2, 95% CI 0.06–0.69; p=0.024) and a higher cancer-specific disease-free survival rate (100% vs. 83.3%; p=0.067). RUTI was safe, with only low-grade injection site reactions and no systemic effects.
Conclusions:
RUTI vaccination prior to intravesical BCG treatment in NMIBC patients is safe and effectively modulates the BCG-induced immune response, promoting a more balanced effective/suppressive response. This novel approach has the potential to significantly improve clinical outcomes in the management of NMIBC. Clinical trial information:
NCT03191578
.
Concurrent pembrozulimab and radiation treatments in the management of locally advanced bladder cancer in cisplatin-ineligible patients.
Authors: Gupta Niraj K. , Liebross Robert H. , Clark Jainie , Gupta Aneesh , Leagre Christopher , Pike Scott , Dugan Thomas , Ney Kenneth , Fitzik Markus , Tumati Vasu
Published: February 2025

817

Background:
Pembrolizumab (P) is commonly used to treat cisplatin-ineligible patients with locally advanced bladder cancer. We previously reported a potential synergistic effect of concurrent radiation and immunotherapy, https://doi.org/10.1200JCO.2020.38.15_suppl.e17020. Here, we present our updated experience with this combination.
Methods:
After transurethral resection of bladder tumor (TURBT), patients received Pembrolizumab 200 mg IV every 3 weeks and radiation treatments, starting 1 week after Pembrolizumab initiation. A total of 64-65 Gy was delivered to the bladder and pelvis. Pembrolizumab was continued for 1 year. Response was assessed by follow-up cystoscopies and serial imaging studies.
Results:
Between October 2021 and May 2023, 14 patients with locally advanced bladder cancer (cT2-T4 or LN+ve) were treated. Median age was 74 years (range 62-91), with a male-to-female ratio of 9:5. ECOG performance status was 0-1 in 5 patients, 2 in 7 patients, and 3 in 2 patients. All patients completed radiation treatments, while 10 patients completed 1 year of Pembrolizumab, 3 patients completed 6-12 months, and 1 patient received less than 6 months. Follow-up cystoscopy was performed in 12 patients, with 7 (58.3%) showing a complete clinical response. Grade 3/4 immune-related adverse events (irAEs) occurred in 1 patient. At a median follow-up of 16 months (range 6-23 months), 9/14 patients (64.2%) remained without evidence of distant disease, 3/14 patients (21.4%) had oligometastatic disease treated with stereotactic body radiation therapy (SBRT) and are now without distant disease, and 2/14 patients (14.4%) developed multiple distant metastases.
Conclusions:
Concurrent radiation and immunotherapy is an effective option with a favorable side-effect profile for cisplatin-ineligible patients with locally advanced bladder cancer. Incorporating other non-chemotherapeutic agents, such as antibody-drug conjugates, into concurrent radiation-immunotherapy combinations warrants further investigation.
Genome-scale metabolic reconstruction of urinary microbiome: Pathway for personalized medicine.
Authors: Wang Betty , Nandwana Devika , Sindhani Mohit , Weight Christopher , Almassi Nima , Packiam Vignesh , Kutikov Alexander , Geynisman Daniel M. , Ghatalia Pooja , Abbosh Philip , Bukavina Laura
Published: February 2025

822

Background:
The human microbiome significantly influences the efficacy and safety of various medications. To integrate microbial metabolism into precision medicine, it is crucial to develop strain- and molecule-specific computational models that can predict a patient's microbiome's ability to metabolize chemotherapy drugs. This study evaluates the potential of urine, pellet, and supernatant samples to identify microbial profiles and metabolizing genes in patients with bladder cancer.
Methods:
Catheterized urine, pellet, and supernatant samples from six patients (5 males and 1 female) with bladder cancer were analyzed to identify microbial species and strains, assess drug gene abundance, and predict drug metabolism. Whole-genome sequencing (WGS) was performed, and gene annotation was conducted using the PubSEED platform. Biosynthetic pathways were identified following the KEGG PATHWAY resource, and AGORA2 reconstruction was used for final metabolic reactions.
Results:
WGS revealed a diverse microbial community, with 1,024 species unique to urine, 386 unique to pellet, and 1,861 species common to both. The most prevalent species, Enterococcus faecalis and Staphylococcus epidermidis, accounted for over 60% of the microbial population in both urine and pellet samples. A detailed comparison of OTU abundance between paired urine and pellet samples showed significant variations in microbial composition, yet a strong correlation between the two sample types. The net metabolizing capacity of 13 chemotherapy-drug metabolites was assessed among the six patients. Mean flux calculations indicated highly variable metabolism of gemcitabine (median 773.57, IQR 380-1056), SN38 (irinotecan) (median 770.24, IQR 10.1-2234.5), and bile salt hydrolase (median 130.80, IQR 9.8-318.2). These findings highlight the microbiome's extensive role in influencing chemotherapy drug pharmacokinetics.
Conclusions:
This study demonstrates the potential of microbiome profiling in informing precision medicine, suggesting that microbiome modification could enhance chemotherapy drug pharmacokinetics and improve patient outcomes. Further research is needed to validate these findings and refine microbiome-based precision medicine in oncology.
DNA damage repair alterations as predictive biomarker for platinum-based chemotherapy in metastatic urothelial cancer.
Authors: Sternschuss Michal , Paynter Alexander , Xu Wenxin , Nichols Chelsea , Hoppe Jennifer , Davis Nancy B , Jiang Di Maria , Shah Neil J.
Published: February 2025

853

Background:
DNA damage repair gene alterations (DDRa), especially
ERCC2
mutations, have been associated with improved clinical outcomes in patients with urothelial cancer (UC) treated with cisplatin-based neoadjuvant chemotherapy. The predictive value of DDR alterations for platinum-based chemotherapy in metastatic disease is not well-defined.
Methods:
We analyzed the American Association of Cancer Research (AACR) Genomics Evidence Neoplasia Information Exchange (GENIE) Biopharma Collaborative consortium (BPC), including patients with UC treated at 4 academic centers in North America between 2013 and 2018, with Next Generation Sequencing (NGS) data available. We assessed overall survival among patients treated with first line platinum-based chemotherapy for metastatic UC, and compared the outcomes based on DDRa status using Cox models adjusted with risk-set adjustment for delayed entry. DDRa were defined as any mutation defined as “likely oncogenic” or “oncogenic” in OncoKB for the genes
ERCC2, ERCC5, BRCA1, BRCA2, RECQL4, ATM, ATR, RAD51C
and
FANCC
.
Results:
Of 716 patients with UC, 103 (14%) had any DDRa, and 32 (4.5%) had an
ERCC2
mutation. Among 566 patients (79%) who developed metastatic disease at any time during follow up, median age was 66 years, 22% were female and 25% had upper tract UC. The median overall survival (mOS) from diagnosis of metastatic disease was 15.1 months (95% CI 12.6-18.6). For patients treated with first line platinum-based chemotherapy (n=258), the presence of DDRa was associated with significantly improved mOS compared with absence of DDRa: 22.7 versus 11.2 months, hazard ratio (HR) 0.54 (95% CI 0.34-0.86, p=0.009). Similar trends were seen when analyzing patients treated with cisplatin or carboplatin, separately.
Conclusions:
DDRa were associated with improved survival in metastatic UC patients treated with platinum-based chemotherapy. Further studies are needed to explore the prognostic and predictive value of DDRa as the role of platinum-based chemotherapy evolves in the enfortumab vedotin and pembrolizumab era.

DDRa
No DDRa

First Line treatment for metastatic UC
N
Median OS months (95% CI)
N
Median OS months (95% CI)
HR (95% CI)
P value

Any platinum-based chemotherapy
32
22.7 (14.5, 66.9)
226
11.2 (9.4, 15.1)
0.54 (0.34, 0.86)
0.009

 Cisplatin-based chemotherapy
22
25.9 (14.5, NR)
142
13.6 (10.4, 18.8)
0.57 (0.32, 1.01)
0.06

 Carboplatin- based chemotherapy
10
17.4 (7.26, NR)
84
9.9 (6.6, 12.7)
0.53 (0.25, 1.17)
0.12

CI= Confidence interval; DDRa= DNA damage repair alteration; HR=Hazard ratio; NR=Not reached; OS= Overall survival; UC= Urothelial Carcinoma.
Assessment of pathologic responses from unstructured pathology reports using large language models.
Authors: Popli Swati , Anjum Muhammad Umair , Naqvi Syed Arsalan Ahmed , Jain Prateek , Singh Parminder , Zakharia Yousef , Riaz Irbaz Bin
Published: February 2025

866

Background:
Emerging data suggests that Language Models (LLMs) provide an unprecedented opportunity to extract critical data from the unstructured pathology reports. However, the performance of state of art (SOTA) models on clinically meaningful tasks such as assessment of pathologic responses in patients receiving neoadjuvant chemotherapy (NAC) in muscle invasive bladder cancer(MIBC) is not well known.
Methods:
This retrospective cohort included patients with pathologically confirmed Muscle-Invasive Bladder Cancer from the year 2018 to 2024. Selected patients included those who underwent Neoadjuvant chemotherapy followed by definitive cystectomy at Mayo Clinic. Gold standard labels were manually curated by trained clinicians. The state of the art (SOTA) LLM – GPT4 – was utilized using a structured zero-shot prompt to extract relevant phenotypic variables such as tumor site, tumor histology and additional histological variants if any, presence of in-situ / invasive carcinoma, presence of lamina propria / muscularis propria / lympho-vascular / perineural invasion, and T-stage from unstructured pathology reports. Structured prompts were iteratively developed for each data variable and validated using ~5% of the total dataset. The extracted variables were manually compared and labelled as True positive / True negative / False positive / False negative. Final performance was assessed against a held-out expert annotated test dataset using evaluation metric (accuracy).
Results:
A total of 200 reports from 99 patients were extracted by the LLM. Of the 200 reports, 41 duplicate / other pathology reports (e.g. – autopsy, cholecystectomy, etc.) were removed during final assessment. Significant characteristics such as tumor site, histology, and additional histology variant had an accuracy of 89%, 87%, and 91% respectively. Notably, accuracy of detection of in-situ versus invasive carcinoma was 70% versus 91%. Specific variables such as lamina propria / muscularis propria invasion / T-stage / lympho-vascular invasion / perineural invasion were answered with the accuracy of 75%, 75%, 67%, 90%, and 94% respectively.
Conclusions:
LLMs have the potential to extract critical data from unstructured pathology reports and automate assessment of pathologic responses in MIBC patients receiving NAC. Iterative improvements in performance can be achieved by improving prompt design using expert clinical input. This process can be potentially scaled to automate cancer registries.
Phase 3 OMAHA-004 study of CYP11A1 inhibitor opevesostat versus next-generation hormonal agent (NHA) switch in patients with metastatic castration-resistant prostate cancer (mCRPC) after 1 prior NHA.
Authors: Gratzke Christian , Vile Donald Charles , Chen Zheng Hong , Garratt Chris , Poehlein Christian Heinrich , Todoric Jelena , Fizazi Karim
Published: February 2025

TPS301

Background:
Androgen receptor (AR) somatic mutation activation is a resistance mechanism to AR-directed therapies (ADT) in mCRPC. Upstream targeting of androgen biosynthesis may provide a therapeutic advantage over available AR-directed therapies in patients with mCRPC. Opevesostat (MK-5684; ODM-208) is an oral, nonsteroidal inhibitor of cytochrome P450 11A1 (CYP11A1), a catalyst of the first and rate-limiting step of steroid biosynthesis. By blocking the first step of the enzymatic pathway, opevesostat has the potential to inhibit all steroid hormones involved in AR signaling activation. In the phase 1/2 CYPIDES study, opevesostat had antitumor activity in patients with heavily pretreated mCRPC, especially in those with AR ligand binding domain (AR-LBD) mutations (1). The randomized, open-label, phase 3 OMAHA-004 trial (NCT06136650) will evaluate the efficacy and safety of opevesostat versus abiraterone or enzalutamide in patients with molecularly unselected mCRPC previously treated with 1 prior NHA.
Methods:
Eligible patients have mCRPC that progressed during ADT ≤6 months before screening and during/after 1 NHA for hormone-sensitive prostate cancer or non-mCRPC. Approximately 1500 patients (375 with, 1125 without AR-LBD mutations) will be randomly assigned 1:1 to receive opevesostat 5 mg PO BID (+ dexamethasone 1.5 mg and fludrocortisone 0.1 mg PO QD) or abiraterone acetate 1000 mg PO QD (if prior enzalutamide/darolutamide/apalutamide) or enzalutamide 160 mg PO QD (if prior abiraterone). Primary endpoints are radiographic progression-free survival per Prostate Cancer Working Group 3 (PCWG3)-modified RECIST v1.1 by blinded independent central review (BICR) and overall survival in AR-LBD mutation–positive and –negative disease, separately. Secondary endpoints include time to initiation of first subsequent anticancer therapy or death; objective response rate and duration of response per PCWG3-modified RECIST v1.1 by BICR; and safety. Recruitment is ongoing. 1. Fizazi et al.
NEJM Evid.
2024. Clinical trial information:
NCT06136650
.
ProstACT GLOBAL: A phase 3 study of
177
Lu-rosopatamab (TLX591) with and without the best standard of care for patients with PSMA expressing metastatic castration-resistant prostate cancer progressing despite prior treatment with a novel androgen axis drug.
Authors: Sartor Alton Oliver , Tagawa Scott T. , Lenzo Nat , Cade David , Agarwal Neeraj
Published: February 2025

TPS303

Background:
The treatment of advanced prostate cancer (PC) is challenging, with undesirable side effects that impact patient quality of life. Radioimmunotherapy (RIT) can localize therapy to specific tumor cells in multiple organs to reduce or eliminate damage to normal tissue. The cell surface glycoprotein prostate-specific membrane antigen (PSMA) is an ideal therapeutic target as it is highly expressed by malignant prostate cells. There is a strong rationale for further investigation of the
177
Lu-labeled, chelator-conjugated antibody,
1
77
Lu-rosopatamab, as a potential first-line RIT candidate for the treatment of PC.
Methods:
This multinational, multicenter, prospective, randomized, open label phase 3 study will have 2 parts: a dosimetry and safety lead-in (n=30) and a randomized treatment expansion (n=490). In Part 1, patients will be divided into 3 groups (n=10 each) to receive 2 single intravenous (IV) injections of 76 millicuries (mCi) each, 14 days apart, of
177
Lu-rosopatamab with best standard of care (SoC) combinations with abiraterone, enzalutamide, or docetaxel to fully characterize biodistribution and safety profiles of
177
Lu-DOTA-rosopatamab + SoC combinations. SoC received will be determined prior to treatment with
177
Lu-rosopatamab. In Part 2, patients will be enrolled in a 2:1 ratio to receive either the best SoC or 2 single IV injections of 76 mCi each (equivalent to a 45 mCi/m
2
dose in a standard 1.7m
2
individual) of
177
Lu-rosopatamab, given 14 days apart, plus best SoC. SoC will be determined prior to randomization, and a change in planned SoC will not be permitted. Eligible patients must have PSMA-expressing metastatic castration-resistant PC (mCRPC) that have progressed despite prior therapy with either enzalutamide or abiraterone plus prednisone, and 1 line of prior taxane therapy or have refused or are ineligible for taxanes. Patients must have adequate organ function including at least 150x10
9
/L platelets, hemoglobin 10 g/dL, and have PSMA-positive disease on
68
Ga-PSMA-11 PET/CT imaging as confirmed by a central reader. Key exclusion criteria include small cell histology, increased risk of hemorrhage or bleeding, known brain or hepatic metastases, or history of stroke, seizure, or treatment with radioisotopes within 6 months prior to randomization. The primary endpoint is radiographic progression-free survival. Key secondary endpoint is OS. Additional secondary endpoints include 5-year overall survival, tumor objective response rate, time to symptomatic skeletal event, and health-related quality of life. Clinical trial information:
NCT04876651
.
The directional control of phototaxis in sea stars (Protoreaster nodosus)
Authors: Po Theodora , Korob Lenny , McHenry Matthew J.
Published: February 2025

Sea stars control hundreds of tube feet to navigate their environment with a rudimentary nervous system. Tube feet are capable of responding to stimuli without descending nervous commands and it is therefore unclear to what extent tactic orientation emerges through the collective action of the tube feet or is guided by central control. We therefore performed behavioral experiments to test models of neuromechanical control in a sea star (Protoreaster nodosus). We found that animals moved rapidly along relatively straight trajectories when exposed to light, but slowly crawled along circuitous paths in random directions in the dark. To remove mechanical interactions with the substrate, we measured the kinematics of tube feet in inverted sea stars that exhibited crawling when in contact with the water's surface. The tube feet throughout the body of these animals moved with power strokes in a similar direction when the animals were exposed to light, which is consistent with central control. This contrasts the variety of directions for power strokes exhibited without illumination. These findings support of a model of navigational control where directionless body motion emerges from collective mechanics in the dark, but is guided by the nervous system when exposed to light. In this manner, sea stars navigate through a combination of collective and central control.
The history of Chaos Magic
Authors: Μελετιάδης Βασίλειος
Published: February 2025

Στόχος αυτής της διατριβής είναι να δοθεί μια αποδοθεί λεπτομερώς η ιστορία του chaos magic, από το 1976 έως το 2000, στη Μ. Βρετανία, τη Γερμανία και τις Ηνωμένες Πολιτείες. Το chaos magic είναι ένα αποκρυφιστικό ρεύμα και φιλοσοφία που ξεκίνησε στο Λιντς της Αγγλίας τη δεκαετία του 1970 από τους αποκρυφιστές Ρέι Σέργουιν και Πίτερ Κάρολ, οι οποίοι ίδρυσαν και τον πρώτο κύκλο chaos magic με όνομα Illuminates of Thanateros (IOT). Αφενός δίνεται έμφαση στα μέλη του κύκλου και τις δραστηριότητές τους καθώς και στην εξάπλωση του chaos magic έξω από το IOT. Αφετέρου, το chaos magic μελετάται εδώ εντός του πλαισίου ενός διευρυμένου αποκεντρωμένου δικτύου το οποίο ορίζεται ως "Σκηνή του Χάους". Κύρια χαρακτηριστικά της σκηνής είναι ο ενθουσιασμός για την έννοια του Χάους, τόσο σε κοινωνικό όσο και σε κοσμολογικό επίπεδο. Πιο συγκεκριμένα, η διατριβή εξετάζει τη σχέση με ταξύ του chaos magic και των μουσικών υποκουλτουρών που απαρτίζουν τη Σκηνή του Χάους, όπως η πανκ, η αναρχο-πανκ, η βιομηχανική, και η ηλεκτρονική μουσική. Εξετάζοντας το chaos magic κάτω από το πρίσμα της δημώδους μουσικής ανακαλύπτουμε σημαντικές πτυχές της κουλτούρας στην οποία κινούνταν οι ακόλουθοι του chaos magic, των πολιτικών και κοινωνικών τους ανησυχιών, και του επαναστατικού τους οραματισμού.
Ουσία, λόγος, μίμηση
Authors: Δημόπουλος Αντώνιος
Published: February 2025

Διατελούμε υπό το καθεστώς µίας γλώσσας της οποίας τα φωνολογικά στοιχεία εγγράφονται σε µία γραφή τόσο στενά συνυφασµένη µαζί τους, ώστε η σκέψη µας µε δυσκολία θα µπορούσε να προσεγγίσει ρυθμούς και επίπεδα οργάνωσης έξω από το καθεστώς της γραμμικότητας του συμβόλου. Η διαδικασία της γραµµοποίησης των συμβόλων είχε, άλλωστε, τη σηµασία ότι συνέβαλε καθοριστικά, από κοινού µε την εδραίωση των συστημάτων γραµµικής σηµειογραφίας ―συστημάτων που δεν έπαψαν να αναδιαρθρώνονται, να τροποποιούνται και να μετασχηματίζονται, από τις πρώτες μαρτυρίες της μεσοποταμιακής γραφής έως το αλφάβητο και τις σύγχρονες τεχνικές συμβολισμού στο χώρο της πληροφορικής―, στην καθιέρωση μίας γραμμικής κανονιστικής πρόληψης, η οποία διέπει ενιαία τη δυτική αντίληψη της γλώσσας, την κοινότυπη έννοια του χρόνου και τη λογική. Αν ο γραμμισμός δεν κατάφερε τελικά να κυριαρχήσει πλήρως, τούτη η αδυναμία ανάγεται στα ίδια αίτια που δεν επέτρεψαν στον φωνητικό γραφισμό να πραγματώσει την πληρότητά του σε μία γλώσσα, της οποίας η συμβολική λειτουργία θα συντόνιζε όλο το φάσμα της εφικτής εμπειρίας. Παράλληλα, οι σύγχρονες προκλήσεις της ψηφιακής εποχής και των νέων τεχνολογιών στα πεδία της πληροφόρησης και της τεχνητής νοημοσύνης απαιτούν ολοένα και πιο επιτακτικά την αναθεώρηση των κλασικών κατηγοριοποιήσεων. Ανατέμνοντας την ιστορικο-θεωρητική συνενοχή του σημείου, της γραμμής και της ουσίας, το εισαγωγικό τμήμα αυτής της μελέτης συνδυάζει την ιστορικο-κριτική εργασία με μία σειρά κινήσεων που αποσκοπούν στη διερεύνηση νέων δυνατοτήτων εννοιολόγησης. Αυτές οι δυνατότητες υποβάλλονται σε συστηματική αξιοποίηση στο κύριο μέρος της μελέτης μας, όπου η ιστορική μέριμνα συνέχεται από μία συστηματική αναφορά σε ό,τι θεωρείται παραδειγματικό και φέρει αξία προτύπου. Έχοντας διασχίσει το κατώφλι της αρχαϊκής εποχής, επικεντρωνόμαστε διαδοχικά στα δύο κυρίαρχα παραδείγματα της δυτικής φιλοσοφικής παράδοσης, πλατωνικό και αριστοτελικό. Πρόκειται για τη στιγμή που οι κλασικές σημειολογικές αξίες θα δεχτούν τις πρώτες θεμελιώδεις επεξεργασίες. Και ενώ είναι αλήθεια ότι η παραδειγματικότητα αυτών των υπογραφών δεν θα μπορούσε να αμφισβητηθεί, η επίκλησή της σηματοδοτεί για μας κάτι περισσότερο από την κωδικοποιημένη μνήμη ενός συστήματος αξιών ή τη γενική αναφορά, παιδαγωγικού ή οικονομικού τύπου, στην πηγή των κλασικών κατηγοριών της ιστορίας.
Heavy Metal Contamination: Sources, Health Impacts, and Sustainable Mitigation Strategies with Insights from Nigerian Case Studies
Authors: Laoye Babafemi , Olagbemide Peter , Ogunnusi Tolulope , Akpor Oghenerobor
Published: February 2025

Heavy metal contamination has gradually become a very much important significant global issue due to its continual existence in the environment and bioaccumulation in the ecosystems, posing deleterious risks to human health. This review aims to investigate the sources, pathways, and toxicological impacts of heavy metals such as cadmium, lead, mercury, and arsenic, elucidating their health consequences and plausible mitigation strategies. Furthermore, the review explores the dual origins of heavy metal contamination; natural geological processes and anthropogenic activities such as industrial emissions, mining, and agricultural practices. These heavy metals sip into soil, water, and food chains, leading to bioaccumulation, bio-magnification and causing significant health risks, including cardiovascular diseases, neurological disorders, and reproductive toxicity. Additionally, the addition of indigenous case studies from Nigeria, such as lead poisoning in Zamfara State and contamination in the Great Kwa River of Cross Rivers State underscores the disproportionate impact of heavy metal pollution in developing nations. These case studies reveal the socio-economic and environmental dimensions of the issue, providing a contextual understanding of region-specific vulnerabilities and health outcomes. To address these problems, the review evaluates already existing mitigation strategies, including chelation therapy and phytoremediation, while proposing sustainable, cost-effective solutions for reducing exposure and mitigating impacts. It emphasizes the importance of integrative approaches involving policy, community engagement, and technological innovations to fight heavy metal contamination effectively. In conclusion, this seminar contributes to the understanding of heavy metal toxicity, giving and showcasing very much important insights into the sources and health implications of contamination. By integrating theoretical perspectives with practical solutions, this review provides a robust framework for informing policy makers and advancing sustainable environmental management practices.
Sketch of a novel approach to a neural model
Authors: Scheler Gabriele
Published: February 2025

There is room on the inside. In this paper, we lay out a novel model of neuroplasticity in the form of a horizontal-vertical integration model of neural processing. The horizontal plane consists of a network of neurons connected by adaptive transmission links. This fits with standard computational neuroscience approaches. Each individual neuron also has a vertical dimension with internal parameters steering the external membrane-expressed parameters. These determine neural transmission. The vertical system consists of (a) external parameters at the membrane layer, divided into compartments (spines, boutons) (b) internal parameters in the sub-membrane zone and the cytoplasm with its protein signaling network and (c) core parameters in the nucleus for genetic and epigenetic information. In such models, each node (=neuron) in the horizontal network has its own internal memory. Neural transmission and information storage are systematically separated. This is an important conceptual advance over synaptic weight models. We discuss the membrane-based (external) filtering and selection of outside signals for processing. Not every transmission event leaves a trace. We also illustrate the neuron-internal computing strategies from intracellular protein signaling to the nucleus as the core system. We want to show that the individual neuron has an important role in the computation of signals. Many assumptions derived from the synaptic weight adjustment hypothesis of memory may not hold in a real brain. We present the neuron as a self-programming device, rather than passively determined by ongoing input. We believe a new approach to neural modeling will benefit the third wave of AI. Ultimately we strive to build a flexible memory system that processes facts and events automatically.