bluuebunny/crossref_metadata_2025 huggingface dataset:
Assessment of integrated patterns of human-animal-environment health: a holistic and stratified analysis
Authors: Guo Zhao-Yu , Feng Jia-Xin , Ai Lin , Xue Jing-Bo , Liu Jing-Shu , Zhang Xiao-Xi , Cao Chun-Li , Xu Jing , Xia Shang , Zhou Xiao-Nong , Chen Jin , Li Shi-Zhu
Published: March 2023

Background

Data-driven research is a very important component of One Health. As the core part of the global One Health index (GOHI), the global One Health Intrinsic Drivers index (IDI) is a framework for evaluating the baseline conditions of human-animal-environment health. This study aims to assess the global performance in terms of GOH-IDI, compare it across different World Bank regions, and analyze the relationships between GOH-IDI and national economic levels.

Methods

The raw data among 146 countries were collected from authoritative databases and official reports in November 2021. Descriptive statistical analysis, data visualization and manipulation, Shapiro normality test and ridge maps were used to evaluate and identify the spatial and classificatory distribution of GOH-IDI. This paper uses the World Bank regional classification and the World Bank income groups to analyse the relationship between GOH-IDI and regional economic levels, and completes the case studies of representative countries.

Results

The performance of One Health Intrinsic Driver in 146 countries was evaluated. The mean (standard deviation, SD) score of GOH-IDI is 54.05 (4.95). The values (mean SD) of different regions are North America (60.44, 2.36), Europe and Central Asia (57.73, 3.29), Middle East and North Africa (57.02, 2.56), East Asia and Pacific (53.87, 5.22), Latin America and the Caribbean (53.75, 2.20), South Asia (52.45, 2.61) and sub-Saharan Africa (48.27, 2.48). Gross national income per capita was moderately correlated with GOH-IDI (R2 = 0.651, Deviance explained = 66.6%, P < 0.005). Low income countries have the best performance in some secondary indicators, including Non-communicable Diseases and Mental Health and Health risks. Five indicators are not statistically different at each economic level, including Animal Epidemic Disease, Animal Biodiversity, Air Quality and Climate Change, Land Resources and Environmental Biodiversity.

Conclusions

The GOH-IDI is a crucial tool to evaluate the situation of One Health. There are inter-regional differences in GOH-IDI significantly at the worldwide level. The best performing region for GOH-IDI was North America and the worst was sub-Saharan Africa. There is a positive correlation between the GOH-IDI and country economic status, with high-income countries performing well in most indicators. GOH-IDI facilitates researchers' understanding of the multidimensional situation in each country and invests more attention in scientific questions that need to be addressed urgently.

Graphical Abstract
Adherence to standard of care (SOC) therapy for the treatment of metastatic hormone-sensitive prostate cancer (mHSPC): A single-institution analysis.
Authors: Dhillon Puneet , Ornstein Moshe Chaim , Gupta Shilpa , Nizam Amanda , Gilligan Timothy D. , Martin Allison , Bonham Amanda , Maroli Kimberly , Wee Christopher Eing
Published: March 2023

103

Background: Androgen deprivation therapy (ADT) has been the backbone of treatment for mHSPC for decades. In recent years, multiple randomized controlled trials demonstrating an overall survival (OS) benefit of combination treatment (e.g. ADT + novel hormonal agent and/or chemotherapy) has made this the current SOC. Large real-world reports have shown a significant number of patients are still being treated below the SOC with ADT alone, but these databases do not include patient level data to help understand the rationale for treatment decisions. We reviewed our institution’s treatment patterns for mHSPC to better understand why some patients are being treated with ADT alone. Methods: We conducted a retrospective analysis on patients who initiated treatment for mHSPC from 2017-2021 at Cleveland Clinic. Patient characteristics were recorded, including age and histology. Treatment characteristics, including location of treatment, treatment regimen, and treatment rationale (if not treated with SOC) were noted. Results: Four hundred forty-nine patients were included, with diagnosis of metastatic disease made at a median of 63 years, of which 446 started treatment with systemic therapy. The vast majority of patients were managed by a medical oncologist (95.5%). About half of the patients (49.8%) received treatment at the main campus, with the remaining patients being treated at an affiliated regional hospital (28.7%) or outpatient medical center (21.5%). Additional characteristics are shown. Out of the 446, 40 (9.0%) patients received ADT alone. Reasons for ADT monotherapy included patient preference (n = 13), cost (n = 2), and poor functional status/comorbidities (n = 4). Twenty (50%) of the patients who got ADT alone had no documented rationale for why this treatment plan was elected. One patient was lost to follow-up. For patients who received only ADT, 12 were treated at main campus, 20 were treated at a regional hospital, and 8 were treated at an outpatient medical center. Conclusions: At our institution, adherence to treatment up to SOC for mHSPC was better than previous real-world reports. There were documented reasons for not treating mHSPC up to SOC combination therapy for half of the patients who got ADT monotherapy. It remains unclear why the remaining half did not get combination therapy up to the SOC. [Table: see text]
First UK experience of apalutamide in metastatic and non-metastatic prostate cancer outside of clinical trials.
Authors: Das Prantik , Mohammed Rania , Sarwar Naveed , Din Omar , Jain Ankit , Davies Jessica , Mugunthan Thangrarajh , Nair Ajith , Ghose Aruni , Bandyopadhyay Seheli , Krishnappa Roopesh , Iyer Pooja , Jones Lauren , Vasdev Nikhil , Moldawa Maja , Devine Rebecca , Hughes Robert , Sharma Anand
Published: March 2023

106

Background: Apalutamide plus androgen deprivation therapy(ADT) has been approved as a treatment option for castrate resistant non metastatic prostate cancer (nmCRPC) with a high risk of developing metastatic disease. It has also demonstrated benefit in patients with metastatic, castration-sensitive prostate (mHSPC) cancer, with improvement in overall and radiographic progression–free survival. Here we report our first experience of using Apalutamide in real life clinical practice. Methods: A cohort of 108 patients from 5 UK centres were included, among them 68 were metastatic and 40 non metastatic. All patients were treated with Apalutamide 240 mg along with ADT until disease progression. The primary endpoint was objective rate (ORR) and secondary endpoints included treatment duration and safety. Results: The median age for the whole cohort was 71 years (interquartile range 43-91), 73 years for nmCRPC and 69 years for mHSPC respectively. 81% had biopsy proven malignancy. A total of 11.7% with mHSPC had received prior radical treatment (prostatectomy or radiotherapy for localised disease), compared to 92.5% patients in the non-metastatic cohort. PSA reached undetectable levels (<0.04 ng per ml) in 67% of the patients in the metastatic and 60% in non-metastatic subset respectively. In patients with mHSPC, who had radiological assessments performed, the response rates at 6 months were as follows: partial response (24%), stable disease (74%) and progressive disease (4%).39% of the whole cohort, reported grade 2 and above toxicities. The commonest were skin rash, thyroid dysfunction, hypertension, lethargy and hot flushes. Adverse events led to discontinuation in 1 patient and dose reduction in 1 patient. Conclusions: Our experience of using Apalutamide has shown good biochemical and radiological response in both nmCRPC and mHSPC. Treatment was well tolerated with low rates of treatment discontinuation. Further follow up of these patients will guide us in terms of overall survival.
Association of baseline inflammatory biomarkers with outcomes in penile squamous cell carcinoma (pSCC) treated with immune checkpoint inhibitors (ICI).
Authors: Zhuang Tony , Goyal Subir , Brown Jacqueline T , Carthon Bradley Curtis , Kucuk Omer , McClintock Greta Russler , Yantorni Lauren Beth , Bilen Mehmet Asim , Master Viraj A. , Nazha Bassel
Published: March 2023

11

Background: Penile squamous cell carcinoma (pSCC) is a rare neoplasm with a poor prognosis and a need for biomarkers to guide treatment selection. We report an association of baseline inflammatory markers with outcomes in pSCC treated with immune checkpoint inhibitors (ICI). Methods: We performed a retrospective review of patients with pSCC from 2012-2022 at the Winship Cancer Institute at Emory University. Demographics, disease characteristics, and optimal cutoffs of biomarkers prior to ICI initiation were described. Neutrophil-to-lymphocyte (NLR), monocyte-to-lymphocyte (MLR), platelet-to-lymphocyte (PLR), and neutrophil-to-eosinophil ratios (NER) were obtained from complete blood count data. Clinical benefit with ICI was defined as complete response, partial response, or stable disease based on RECIST 1.1 criteria. Overall survival (OS) and progression-free survival (PFS) were assessed by the Kaplan-Meier method and univariate Cox regression (UVA) using SAS software with significance level set at p<0.05. Results: Twenty-one patients were included in which 71.4% were white and 28.6% were black. Median age at ICI initiation was 56 years (38-76). Most patients (65%) had an ECOG PS ≥2. Four patients (19.1%) had clinical benefit at best response to ICI. Most patients (76.2%) had disease progression and 14.3% were alive at last contact. Median OS was 8.4 months (mo) (95%CI: 2.3-15.7), and median PFS was 2.0 mo (95%CI: 1.3-3.2). Of 9 patients with available HPV status, 8 were HPV+. Of 12 patients with available PD-L1 status, 8 were PD-L1+. Median follow-up was 8.4 mo and median time to ICI treatment from diagnosis was 15.6 mo. High baseline NLR, MLR, PLR, and NER above optimal cut were significantly associated with shorter OS on UVA (Table,all p<0.05). High baseline NLR was associated with shorter PFS (p=0.003). Baseline NLR groups were similar except for age and without differences in race, ECOG, BMI, PD-L1, and HPV status. Conclusions: Our real-world analysis reports a potential association of baseline inflammatory biomarkers with clinical outcomes in ICI-treated pSCC. More prospective and multicenter studies are needed for further confirmation. [Table: see text]
Cascade genetic testing (CGT) female first-degree relatives (FDR) of men with germline BRCA2 mutations (gBRCA2mut) and prostate cancer (PCa): A cost-effectiveness analysis.
Authors: Carletti Alexie A , Caughey Aaron B , Sokolova Alexandra
Published: March 2023

110

Background: g BRCA2mut are associated with increased risk of PCa, breast cancer (BC), and ovarian cancer (OC). ~5% of men with metastatic PCa have g BRCA2mut. CGT is recommended for their relatives as there are implications for cancer prevention and early detection strategies. Little is known about CGT initiated by men with PCa. Here we evaluate the cost-effectiveness of CGT in FDR of men with PCa and g BRCA2mut. Methods: A decision-analytic model was created with TreeAge software to compare BC and OC outcomes for female FDRs who underwent CGT for g BRCA2mut versus no CGT. Our theoretical cohort contained 100,000 females, a conservative estimate of patients who could benefit from CGT. We used literature derived estimates to determine the percentage of patients that would pursue risk-reducing mastectomy, risk-reducing salpingo-oophorectomy, both surgeries, or surveillance after CGT. Outcomes included BC or OC diagnoses, survivorship, and cancer death. We derived all probabilities, costs, utilities, and life expectancies from the literature and discounted quality adjusted life years (QALYs) at a rate of 3%. Incremental cost-effectiveness (ICER) was calculated to determine the cost per QALY gained and set the willingness-to-pay threshold at $100,000/QALY. We assessed the robustness of the model with sensitivity analyses. Results: In our theoretical cohort, CGT of female FDRs resulted in 12,910 less BC diagnoses and 6,360 less BC deaths. CGT was associated with lower BC death rates (26.1%) compared to no CGT (35.8%). CGT was not associated with reduction in OC diagnoses or deaths. Our model resulted in lower costs and higher QALYs (a dominant strategy) among the CGT cohort with an ICER of -$4,190.10 per QALY, saving an estimated $595 million. We found that CGT in females was the dominant strategy in 100% of the samples, once uncertainty was incorporated into our model inputs via Monte Carlo simulation. The cost-effectiveness of CGT for male FDRs will be presented at the meeting. Conclusions: In this study, CGT of female FDRs of men with PCa and g BRCA2mut was the dominant strategy to improve BC outcomes, including increased survivorship and reduced BC development. Despite a lack of demonstrated benefit for OC, CGT was associated with reduced costs and increased QALYs. CGT for female FDRs of patients with PCa and g BRCA2mut may be a cost-effective approach for identifying and informing individuals with potentially harmful mutations. [Table: see text]
Pembrolizumab (Pem) in metastatic castration-resistant prostate cancer (mCRPC): Experience from a comprehensive cancer center.
Authors: Roy Arya Mariam , Farmer Bailey , Muthusamy Kumarasamy Vasanthan , Jatwani Karan , Levine Ellis Glenn , Chatta Gurkamal S. , Gopalakrishnan Dharmesh
Published: March 2023

113

Background: The prognosis of refractory mCRPC remains poor despite advancements in therapeutic options. KeyNote-199 demonstrated modest activity of Pem in mCRPC with expected safety profile. We present our real-world experience with Pem in mCRPC. Methods: We conducted a retrospective review of mCRPC patients treated with Pem at our institution from 1/1/2017 to 10/1/22. Baseline demographic, clinicopathologic, and genomic characteristics were recorded. PSA and radiographic responses were assessed by the study team, and survival distributions estimated using the Kaplan-Meier method. Results: A total of 39 patients were identified – 97% (37) were White, median age was 71 years, 4% (19/35) had a Gleason Score ≥8; 80% (31) had skeletal and 74% (29) had soft tissue metastases at Pem initiation. Overall, patients were heavily pre-treated (median of 7 prior therapies, range 0-8) - 87% (34) had received taxanes, 82% (32) novel antiandrogens, 23% (9) Ra-223, 21% (8) Sipuleucel-T, and 2% (1) Olaparib. Median duration on Pem was 7 months (range = 1-29). Among the 34 evaluable patients, 2 (6%) achieved CR, 2 (6%) had PR, 5 (15%) had stable disease (SD), and 25 (73%) had progressive disease (PD) on radiographic assessment. PSA reduction ≥ 50% was noted in 7/32 (22%) patients. The 4 patients who had radiographic CR/PR had positive predictive biomarkers – Patient 1: CR – MSI-H, high TMB (17.5/Mb); Patient 2: CR – MSI-indeterminate, germline MSH6 mutation; Patient 3: PR – MSI-H, high TMB (28.8/Mb), germline MSH2 mutation; and Patient 4: PR – MSI-S, high TMB (18.3/Mb), PDL1 TPS 100%, positive neuroendocrine markers. Interestingly, patient 3 was switched to ipilimumab + nivolumab after PD on Pem, and subsequently had a CR. None of the evaluated patients with SD or PD had high MSI, TMB, or PDL1 levels. The median overall survival from Pem initiation was 4.4 months (95% CI 3.0-10.2 months). Three (8%) patients discontinued Pem due to immune-related adverse effects (IRAEs); no treatment-related deaths were reported. The most frequent Gr 3 IRAEs are shown. Conclusions: Single-agent Pem demonstrated modest overall efficacy in mCRPC, restricted only to patients with predictive biomarkers. Given the non-trivial risk of IRAEs, financial toxicity, and potential QoL implications, we suggest using checkpoint inhibitors only in appropriately biomarker-selected patients with mCRPC. [Table: see text]
Real world rates of genetic referrals and germline testing in patients with prostate adenocarcinoma at an academic cancer center in southern New Jersey.
Authors: Ambrogi Christopher , Desai Sahaj , Carhart Randi Zukas , Jenab-Wolcott Jenia , Shih Julia Chia-Ying
Published: March 2023

114

Background: Prostate adenocarcinoma is the second leading cause of cancer-related death in men in the United States. A major risk factor is family history, with prostate cancer in a first-degree relative effectively doubling a patient’s risk. However, relying on family history alone fails to identify many patients with clinically relevant cancer-related germline mutations, which can have important prognostic and therapeutic implications for patients and their families. In 2018, the NCCN recommended expanding the germline testing to include all men with high risk, very high risk, regional or metastatic prostate cancer. We sought to identify the rate of genetic testing within this patient population at the MD Anderson Cancer Center at Cooper University Hospital. Methods: The institution database was queried to identify patients with the ICD-10 diagnosis of prostate adenocarcinoma between 01-2019 and 12-2020; the inclusion criteria were age 18 years or older, biopsy-proven prostate adenocarcinoma, and qualification to receive germline genetic testing per NCCN guidelines. A total of 201 patients were screened and 97 cases were analyzed. Results: Of the 97 patients who qualified for genetic testing, 53 were referred to genetics (54.6%). 27 of the 53 patients who met with our genetics team underwent testing (50.9%). Of the 27 patients tested, nine patients (33.3%) were found to have clinically relevant cancer-related germline mutations with therapeutic implications for the patient and/or screening recommendations for the patient and their family members. Conclusions: Overall, the proportion of patients who qualified for and completed genetic testing was low at 27.8%. Of those who completed testing, the rate of detection of a significant germline mutation was high at 33.3%, indicating that a significant proportion of those untested may carry a genetic mutation of clinical importance. Based on these results, we developed an electronic Best Practice Alert that notifies providers if a patient qualifies for a genetic risk evaluation based on his prostate cancer risk. We implemented this system, with reported high utilization demonstrating feasibility of this tool. Preliminary data shows improved rates of referral among prostate cancer patients.
Preliminary findings of G8 and G8-modified as screening tools associated with quality of life in elderly patients with prostate, renal or bladder neoplasms in a Brazilian cancer center.
Authors: Modesto Ingrid Felix Felix , Dettino Aldo A.
Published: March 2023

122

Background: Population aging and cancer increased incidence are a public health challenge, as the elderly vary widely in terms of health status and aging process. Aiming at therapeutic efficacy and minimization of toxicities, treatment should be individualized. To aid in clinical decision and patient (pt) management, screening tools use is recommended, such as the G8 and the G8-modified (G8m), which identify geriatric problems: scored as abnormal when ≤ 14 and ≥6, respectively. These scales include health status self-assessment, which can be investigated by specific tools as EQ-5D-5L. The objective is to compare the G8 and G8m scales as screening tools in Brazilians ≥ 60 years old with urological tumors and describe Quality of Life using the Visual Analogue Scale of EQ-5D-5L (EQ VAS), which scores from 0-100 (higher better). Methods: Sociodemographic data were collected, and scales G8, G8m and EQ-5D-5L were applied to elderly people ≥ 60 years old with urologic cancer diagnosed within 6 months or prior to a change in therapeutic strategy, from Feb to Sep 2022. Statistical analyzes were performed, such as means, median, standard deviation and proportions, as well as comparisons of G8 total score versus G8m, using Kappa Coefficient. Fisher's Exact Test was used to analyze these scores related to sociodemographic data and the Pearson Correlation test to verify the relationship of the scores with the EQ VAS. Results: 43 pt aged ≥ 60 completed G8 with a mean score of 13,7(±2,2), G8m with 7,7 (±6,6) and EQ VAS 81,5 (±14,9). The mean age was 72,7 (±8,7) and 100% were men and 27 (62,8%) were white; furthermore, 9 (20,9%) lived alone. The most frequent cancer type was prostate 34(79,1%), followed by renal 5 (11,6%). 36 (83.7%) pt were changing treatment strategy and 7 (16.3%) had a diagnosis within 6 months. A weak agreement of 72.2% between normal G8 and G8m scores was identified (Kappa = 0.435 and p 0.006). A statistically significant association between normal G8m score and married marital status (p=0.039) was found, however there was no statistically significant association between G8 and G8m scores and comorbidities, smoking or polypharmacy. As well as no statistically significant correlation was found between the G8 and G8m scores with the Quality of Life measured by the EQ VAS. Conclusions: G8 and G8m demonstrated similar results in elderly pt with urologic tumors, identifying pt with frailties that are warranting a complete geriatric evaluation. In addition, this study indicates that it is better to assess quality of life using specific instruments, since the G8 and G8m scores were not correlated with the EQ VAS, although the screening scales included self-rated health. We intend to prospectively evaluate the prognostic power in the short term - 6 months, relating it to the quality of life, by the EQ-5D-5L.
Risk factors for treatment (tx) toxicity and discontinuation among patients (pts) with metastatic castration-resistant prostate cancer (mCRPC) on androgen receptor targeted therapy (ART).
Authors: Chakrani Zakaria , Mellgard George Slade , Mccroskery Stephen , Saffran Nathaniel , Taylor Nicole , Liaw Bobby Chi-Hung , Oh William K. , Tsao Kai , Patel Vaibhav G.
Published: March 2023

135

Background: mCRPC is associated with (a/w) increased mortality among prostate cancer pts and new and safe txs are needed. In recent clinical trials, ARTs improved survival outcomes within this population, however, a significant portion will go on to discontinue tx. We aim to describe reasons for ART tx discontinuation and to identify predictors a/w increased risk of tx discontinuation due to tx toxicity or death. Methods: We performed a single-institution retrospective review of mCRPC pts on ART between 2010 and 2021. We screened for demographics, medical history, ART course, and tx side-effects. Our primary aim was to identify risk factors for tx discontinuation due to toxicity or death. Our secondary aim was to describe ART discontinuation among mCRPC. Fisher’s Exact was used to identify significant predictors of tx discontinuation due to toxicity or death. Significant outcomes were included in a multivariate logistic regression to determine odds ratios. Results: 133 pts with mCRPC started and discontinued ARTs. Among this cohort, 27 pts (20.3%) discontinued tx due to death or toxicity. Reasons for tx discontinuation are described in the table below. Significant predictors of tx discontinuation due to toxicity or death on bivariate analysis included pt-reported sepsis, hypertension (htn), weakness, falls, ECOG ≥2, and hospitalization during tx. Adjusting for confounders, pt-reported falls (OR 2.35; [0.91-2.59]; p=0.009), htn (OR 2.06; [0.94-2.21]; p=0.027), and weakness (OR 1.63; [0.59-2.72]; p=0.007) were a/w an increased risk of pt tx discontinuation from toxicity or death. Conclusions: Our results illustrate that the majority of mCRPC pts discontinued tx due to progression of disease. The data also indicates that mCRPC pts reporting new onset htn, falls, or weakness were more likely to discontinue tx due to toxicity or death. Early monitoring of this population is warranted to prolong duration of tx and prevent unnecessary txs. [Table: see text]
Additional cycles of docetaxel in combination with androgen deprivation therapy (D-ADT) in metastatic hormone-sensitive prostate cancer (mHSPC): Efficacy and feasibility analysis.
Authors: Aydogdu Can , Urban Florian , Tamalunas Alexander , Berg Elena , Götz Melanie , Rodler Severin , Heinemann Volker , Stief Christian , Casuscelli Jozefina
Published: March 2023

185

Background: Several phase III trials have assessed efficacy and safety of 6 cycles of docetaxel combined to androgen deprivation therapy (ADT). This is the current standard of care for a subgroup of patients. We aimed to assess whether treatment beyond 6 cycles of docetaxel prove to be more effective than the standard of care. Methods: We retrospectively analyzed patients with histologically confirmed adenocarcinoma of the prostate and radiologically proven metastatic disease from a large tertiary care center. All patients with mHSPC were treated in first line with ADT in combination with docetaxel (75 mg/m2) (D-ADT) intravenously on the first day of each 21-day cycle. A subset of patients was treated beyond the standard of 6 cycles. Clinical and pathological variables were analyzed, progression free survival on D-ADT (PFS1), progression free survival on subsequent therapy (PFS2) and overall survival (OS) were the endpoints analyzed by log- rank test. Results: Between 2018-2022 a total of 74 mHSPC patients were followed-up for a median time of 13.7 months. Mean age was 66.2 years (range 50.1-82.4), and 79.7% had GS≥8, 73% a CHAARTED high-volume and 76% LATITUDE high risk disease. 43 pts. were treated with ≤ 6 cycles (D-ADTstand) (2.4 % 1-2 cycles; 97.6 % ≥3 cycles; mean 5.3 cycles) and 31 were treated with >6 cycles docetaxel (D-ADTadd) (25.8 % 7-8 cycles; 74.2% ≥9-10 cycles, mean 9.2 cycles). No significant differences were observed in median PFS1 (12.4 vs. 13.7 mos.) and PFS2 (5.4 vs. 9.6 mos.). Median OS in the D-ADTstand group was 39.8 mos., median OS in the D-ADTadd group was not yet reached. Conclusions: While more than 6 cycles of D-ADT in mHSPC proved to be feasible without significant additional toxicity, efficacy is not superior compared to the standard of 6 cycles. Overall survival data is not mature yet, but the benefit of more chemotherapy upfront is debatable and leverages further studies in light of the upcoming triplet combinations in mHSPC, that presumably will render D-ADT obsolete in future. [Table: see text]
Physician-driven artificial intelligence enabled planning for intraprostatic dose escalation in under ten minutes.
Authors: Rayn Kareem , Elliston Carl , Savacool Michelle , Fang Yi , Deutsch Israel , Spina Catherine S. , Kachnic Lisa A. , Yu James B.
Published: March 2023

187

Background: Intraprostatic radiation dose escalation is an area of clinical interest. Dose escalation within the prostate must be balanced with maintaining acceptable dose to the organs at risk, OAR (bladder, rectum, and urethra). Treatment planning therefore requires simultaneous consideration of multiple competing plan optimization goals, for which iterative, interdisciplinary treatment planning tasks may take significant physician, physicist, and dosimetrist time. Semi-automated treatment planning using artificial intelligence has the potential to significantly reduce treatment planning time for technically complex treatments. Methods: A prostate SBRT planning template was created using the Varian ETHOS treatment planning system (TPS) combined with an in-house RapidPlan SBRT prostate model. Prostate dose was prescribed to 36.25 Gy over 5 fractions with 95% coverage to the PTV. To respect standard SBRT normal tissue toxicity constraints while simultaneously escalating intraprostatic dose, the TPS automatically created an intraprostatic boost structure (PTV_SIB), derived from the PTV by excluding OARs with a pre-determined margin. Physicians were trained to perform treatment planning using the prostate SBRT planning template. Treatment planning was performed on 5 unique patients. The time spent from initiation to end of treatment planning and dosimetric parameters were recorded. Results: For each patient, the ETHOS TPS generated two SBRT plans (9 field static IMRT and 3 VMAT arc) with intraprostatic dose escalation in an average of 9.3 minutes [range 8.4-11.8]. Static field and VMAT plans were comparable. PTV_SIB was escalated to above 50 Gy in all cases. Relevant dosimetry for each patient’s static IMRT plan is shown. Conclusions: Physician-driven ETHOS treatment planning was able to produce boosted internal PTV doses using autosegmented volumes. The ETHOS TPS was able to generate dose-escalated plans that reconciled complex OAR and PTV goals within 8-12 minutes. Hence, the ETHOS TPS opens the possibility of rapid physician-driven treatment planning throughput. [Table: see text]
Effect of early PSA decline after starting second-generation hormone therapy in the post-docetaxel setting on cancer-specific survival in metastatic castrate-resistant prostate cancer.
Authors: Lehner Kelly , Ahmed Mohamed E. , Bole Raevti , Andrews Jack R. , Haloi Rimki , Bold Michael S. , Kendi Ayse T. , Karnes R. Jeffrey , Kwon Eugene D. , Bryce Alan Haruo
Published: March 2023

189

Background: The objective of this study is to evaluate the prognostic value of early PSA decline following initiation of second-generation hormone therapy (2nd HT), namely abiraterone acetate or enzalutamide, in the post-chemotherapy setting in patients with metastatic castrate-resistant prostate cancer (mCRPC). Methods: We retrospectively identified 75 m-CRPC patients treated with 2nd HT following docetaxel failure (defined as PSA rise and radiographic progression). Patients were categorized into two groups based on first PSA within 3 months after initiation of therapy: PSA reduction ≥ 50% (Group A) and PSA reduction < 50% (Group B). The primary endpoint was cancer-specific mortality and the secondary endpoint was radiographic progression free survival. Results: There were 75 patients (52 in group A, 23 in group B) in the analytic cohort. Baseline clinical and demographic characteristics, including median age, primary Gleason score risk group, median pre-treatment PSA, disease burden, site of metastases, and pre-treatment ECOG score were not statistically different between the two groups. PSA reduction ≥50% was significantly associated with decreased risk of radiographic disease progression (HR 0.41, 95%CI 0.21-0.80, p = 0.0113) as well as decreased risk of cancer-specific mortality (HR 0.29, 95%CI 0.09-0.87, p = 0.0325). Conclusions: PSA reduction ≥50% within 3 months of starting 2nd HT for patients with mCRPC who have failed first-line docetaxel is associated with significantly improved 3-year cancer-specific mortality and progression free survival. Our data supports the use of PSA as an early prognosticating marker for patient outcomes on this second line therapy. [Table: see text]
The effect of statin use on survival outcomes in patients with metastatic castration-resistant prostate cancer (mCRPC) treated with androgen receptor targeted therapies (ART).
Authors: Mellgard George Slade , Saffran Nathaniel , Chakrani Zakaria , Mccroskery Stephen , Taylor Nicole , Liaw Bobby Chi-Hung , Galsky Matt D. , Tsao Kai , Patel Vaibhav G.
Published: March 2023

194

Background: Statins may reinforce and provide a compounded effect on ART by decreasing cholesterol levels thus decreasing de novo androgen synthesis. We aim to investigate the clinical effect of concurrent statin and ART use on outcomes of mCRPC patients. Methods: We conducted a retrospective analysis on mCRPC patients receiving ART from a single institution. Relevant demographic and clinical data was collected in addition to ART treatment course, statin treatment, and survival outcomes. Our primary outcome was PSA progression free survival (PFS) and our secondary outcomes were overall survival (OS) and associated prognostic factors for both PSA PFS and OS. Chi-squared test and Wilcoxon signed ranked test were used to compare baseline characteristics, and a Cox proportional hazards regression model was used to estimate hazard ratios (HR) with 95% confidence interval (CI) for overall survival (OS) and PSA PFS. Results: 153 patients were included in the analysis between 2010 and 2021. 67 patients (mean age 73.8 years) received concurrent statins and 86 patients (mean age 67.6 years) did not. Median PSA PFS was 37.4 months for patients that received concurrent statins and 17.4 months for patients that did not receive statins. On univariate and multivariate analyses, there was no statistically significance difference between groups for PSA PFS (HR 0.7; CI 0.44-1.1; p=0.122). Median OS was 35.6 months for patients that received concurrent statins and 24.0 months for patients who did not. There was no statistical significance between groups for OS on univariate or multivariate analyses (HR 0.67; CI 0.42-1.06; p=0.087). Conclusions: Although results were not statistically significant, our study illustrates that concurrent statin use exhibits improved time to PSA progression and OS in mCRPC patients. Larger multi-center and further prospective studies are warranted to elucidate the relationship between statin use and overall outcomes in this population.
Impact of vaccination against SARS-CoV-2 on the risk of hospital admission and death among infected patients with urologic cancers: A population-based study in northern Italy.
Authors: Fratino Lucia , Gobbato Michele , Clagnan Elena , Taborelli Martina , Del Zotto Stefania , Toffolutti Federica , Burba Ivana , Tosolini Francesca , Polimeni Joseph , Serraino Diego
Published: March 2023

205

Background: Background: Hospital admission and death of infected cancer patients were investigated according to SARS-CoV-2 vaccination status. Methods: Population-based observational study on 1874 SARS-CoV-2 infected patients with prostate (n=1276), kidney (n=327), and bladder (n=271) cancers. Hazard ratios (HR) and their 95% confidence intervals (CI), adjusted for sex and age, were computed to assess the risk of hospital admission and death of unvaccinated patients as compared to vaccinated ones. Results: 24.5% of patients with prostate, 26.9% with kidney and 29.5% with bladder cancer were unvaccinated. As compared to vaccinated ones, a statistically significant excess risk of hospital admission emerged for unvaccinated ones with prostate (HR=3.33, 95% CI: 2.50-4.55), and kidney (HR=4.35, 95% CI: 2.33-8.33) cancer. The 312 unvaccinated prostate cancer patients were also at a nearly 3-fold higher risk of death than vaccinated ones (HR=2.98, 95% CI:1.89-4.70). Conclusions: Study findings stress the importance of SARS-CoV-2 vaccines in reducing hospital admission and death in patients with urologic cancers, particularly prostate cancer.
Baseline characteristics associated with PSA progression-free survival in patients (pts) with high-risk biochemically relapsed prostate cancer: Results from the phase 3 PRESTO study (AFT-19).
Authors: Aggarwal Rahul Raj , Heller Glenn , Hillman David W. , Xiao Han , Picus Joel , Taplin Mary-Ellen , Dorff Tanya B. , Appleman Leonard Joseph , Weckstein Douglas Jay , Patnaik Akash , Bryce Alan Haruo , Shevrin Daniel H. , Mohler James , Anderson Daniel M. , Rao Arpit , Tagawa Scott T. , Tan Alan , Eggener Scott E. , Ryan Charles J. , Morris Michael J.
Published: March 2023

208

Background: In the Phase 3 PRESTO study, intensified androgen deprivation therapy (ADT) with apalutamide (APA) with or without abiraterone acetate plus prednisone (AAP), administered for a finite treatment period of 52 weeks, prolonged prostate-specific antigen progression-free survival (PSA PFS) in pts with high-risk biochemically relapsed prostate cancer (BRPC). We evaluated baseline factors associated with PSA PFS in this study. Methods: PRESTO is a randomized phase 3, open-label trial in pts with BRPC following radical prostatectomy (RP) and PSA doubling time (PSADT) ≤ 9 months (mo), without distant metastases on conventional imaging (NCT03009981). Pts were randomized 1:1:1 to receive a finite 52-week treatment course with ADT, ADT + APA, or ADT + APA + AAP, stratified by PSADT (< 3 vs 3–9 mo), with post-treatment follow-up. Baseline factors associated with PSA PFS including Gleason sum at RP (6-7, 8, ≥ 9) were analyzed in a post hoc fashion. Results: 504 pts were randomized to ADT alone (N = 167), ADT + APA (N = 168) or ADT + APA + AAP (N = 169). Baseline patient characteristics including Gleason sum at diagnosis, serum PSA and PSADT at study entry, time interval from radical prostatectomy, and receipt of prior radiation (none, adjuvant, salvage) were well balanced across the three treatment arms. At the first planned interim analysis, both experimental arms significantly prolonged PSA PFS compared to the control arm (median 24.9 mo for ADT + APA vs 20.3 mo for ADT, HR = 0.52 (95% CI: 0.35–0.77); median 26.0 mo for ADT + APA + AAP vs 20.0 mo for ADT, HR = 0.48 (95% CI: 0.32–0.71)). Across the study cohort, Gleason sum ≥ 9 at diagnosis was associated with shorter PSA PFS (median 21.9 mo for Gleason ≥ 9 vs. 31.1 mo for Gleason 8 vs. 25.2 mo for Gleason 6-7, log-rank p-value = 0.0409). In addition, within each treatment arm, a shorter observed median PSA PFS was detected for patients with Gleason ≥ 9 prostate cancer. Serum PSA and PSADT at study entry, time from prior radical prostatectomy, and prior radiation were not associated with PSA PFS in the overall study cohort or in individual study arms. Conclusions: Gleason sum ≥ 9 prostate cancer at diagnosis was associated with shorter time to PSA progression following subsequent intensified ADT administered for a finite treatment interval in BRPC. Follow-up is ongoing to integrate genomic profiling of primary prostate cancer tissue with these results and validate with longer term endpoints including metastasis-free survival. Clinical trial information: NCT03009981 .
The comprehensive analysis of relationship between gut microbiome and treatment outcome of androgen deprivation therapy (ADT)-based treatment in patients with metastatic castration-sensitive and -resistant prostate cancer.
Authors: Matsubara Nobuaki , Sakai Shunsuke , Yamashita Riu , Misumi Toshihiro , Shiota Masaki , Eto Masatoshi , Kato Taigo , Osawa Takahiro , Abe Takashige , Shinohara Nobuo , Nishimoto Koshiro , Yasumizu Yota , Tanaka Nobuyuki , Oya Mototsugu , Fujisawa Takao , Horasawa Satoshi , Nakamura Yoshiaki , Yoshino Takayuki , Nonomura Norio
Published: March 2023

213

Background: Preclinical and clinical data from various types of cancer show that the gut microbiome can affect the outcome of treatments with immune checkpoint inhibitors or cytotoxic chemotherapies. However, the relationship between the microbiome and treatment outcomes in prostate cancer has remained unclear. Here, we present a comprehensive analysis of the relationship between the gut microbiome and treatment outcomes from a nationwide genome screening project (MONSTAR-SCREEN 1) in patients with metastatic castration-sensitive and -resistant prostate cancer (mCSPC and mCRPC). Methods: We performed 16S rRNA gene sequencing of fecal DNA from 73 mCSPC and 83 mCRPC patients before treatment. The microbiome data were compared using the Wilcoxon-Mann-Whitney test or Fisher’s exact test. Survival status and therapeutic efficacy of ADT based treatment were prospectively collected and estimated using the Kaplan-Meier method, and the log-rank test was used to compare survival in different strata. Results: Fecal samples from mCRPC had more Klebsiella and Enterobacteriaceae than those from mCSPC, whereas mCSPC had more Akkermansia and Bifidobacterium compared to mCRPC. Prior and concurrent usage of anti-biotics did not affect diversity of the amplicon sequence variants (ASVs), KEGG orthology and metabolism pathway representation. Anti-biotics also did not influence time to treatment failure (TTF) in mCRPC (HR:0.81, 95%CI:0.36–1.78) and mCSPC (HR:1.35, 95%CI:0.55–3.34). mCRPC had more diverse KEGG orthology compared to mCSPC ( p=0.0009), however, no statistical differences were observed in the ASV ( p=0.77) and metabolism pathway representation ( p=0.35) between mCRPC and mCSPC. High ASV tended to be associated with longer TTF rather than low ASV in both mCRPC (Adjusted HR:0.63, 95%CI:0.34–1.10) and mCSPC (Adjusted HR:0.66, 95%CI:0.31–1.40). mCRPC patients with high AVS also showed significant longer PSA-progression free survival than patients with low ASV (HR:053, 95%CI:0.28–0.99). Conclusions: This investigation revealed significant differences in the microbiome status of mCRPC compared to mCSPC. These differences and diversity might influence the outcomes of ADT based treatment in prostate cancer.
Impact of somatic DNA repair mutations on bone-related efficacy endpoints in patients with metastatic castration-resistant prostate cancer (mCRPC): A retrospective analysis.
Authors: Cursano Maria Concetta , Giunta Emilio Francesco , Scarpi Emanuela , Casadei Chiara , Virga Alessandra , Ulivi Paola , Bleve Sara , Brighi Nicole , Ravaglia Giorgia , Pantano Francesco , Santini Daniele , Conteduca Vincenza , De Giorgi Ugo
Published: March 2023

214

Background: Up to 80% of mCRPC have bone metastases and about 25% of metastatic prostate cancer harbor mutations in DNA damage repair defects (DDR). DDR gene mutations are a negative prognostic factor, being associated with short metastasis-free survival and cancer-specific survival. We analyzed the impact of somatic mutations in DDR genes on bone-related efficacy endpoints in mCRPC. Methods: We retrospectively analyzed the mutational status of mCRPC patients per FoundationOne analysis in tissue biopsy or, when it was not possible, in liquid biopsy (performed at the onset of mCRPC). We evaluated the impact of DDR gene mutations on bone-related efficacy endpoints at the time of mCRPC diagnoses, by dividing patients in two main groups (mutated DDR, specifically, mutations in at least one of BRCA1/2, ATM, FANCA, ATR, CHEK2, RAD51, PALB2, and CDK12 genes: group A; wild-type DDR: group B). We investigated differences between the two groups in terms of time from bone metastases onset to death, skeletal metastatic tumor burden (sites and number of lesions), skeletal-related events (SRE) incidence, and time to first on-study SRE. Results: Of the 131 patients with mCRPC enrolled, 115 had bone metastases. Clinical data distribution, according to molecular profile, is presented. There is no difference in terms of sites of metastases and time from bone metastases onset to death between the 2 groups. Mutated DDR status was associated with bone metastases volume (p = 0.0325), but did not affect SRE incidence and time to SRE onset. Conclusions: In our analysis, mutated DDR status was associated with higher bone metastases volume, although a not detrimental effect on the other bone-related efficacy endpoints was observed. [Table: see text]
Effect of neuroendocrine differentiation on therapeutic efficacy of abiraterone and docetaxel as first-line therapy in metastatic castration-resistant prostate cancer.
Authors: Xu Nanwei , Zhao Jinge , Shen Pengfei , Chen Ni , Zeng Hao
Published: March 2023

216

Background: This study aims to explore the prognostic value of neuroendocrine differentiation (NED) in patients with metastatic castration-resistant prostate cancer (mCRPC) receiving abiraterone or docetaxel therapy. Methods: We retrospectively analyzed data of 262 mCRPC patients treated with abiraterone or docetaxel as first-line therapy. NED status was evaluated using prostate biopsy samples at the time of mCRPC by immunohistochemical staining. Kaplan-Meier curves and Cox regression were used to assess the association between NED and treatment outcomes including PSA progression-free survival (PSA-PFS), radiographic progression-free survival (rPFS), and overall survival (OS). Results: In total, NED was confirmed in 100/262 (38.2%) mCRPC patients, with 76/100 (76.0%) and 24/100 (24.0%) men harboring NED<10% and NED≥10%, respectively. In abiraterone treatment, NED was associated with a significantly shorter median PSA-PFS (mPSA-PFS, 7.5-Mo vs. 10.3-Mo, P<0.001), median rPFS (mrPFS, 15.9-Mo vs. 19.5-Mo, P=0.010), and median OS (mOS, 23.2-Mo vs. 34.3-Mo, P=0.014). Likewise, for mCRPC patients receiving docetaxel-based chemotherapy, the positive detection of NED also predicted shorter mPSA-PFS (3.8-Mo vs. 5.9-Mo, P=0.052), mrPFS (8.4-Mo vs. 20.4-Mo, P=0.016) and mOS (13.6-Mo vs. 29.0-Mo, P=0.033). The adverse prognostic trait of NED is consistent in most subgroups. Additionally, patients’ survival outcomes deteriorated as the NED proportion grew in both therapies. Both abiraterone and docetaxel exerted similar and unfavorable efficacy on NED-positive mCRPC patients. Conclusions: For mCRPC patients receiving abiraterone or docetaxel treatment, NED and its proportion were critical prognostic factors. NED detection at mCRPC might aid in predicting patients’ outcomes and optimizing treatment decisions.
Androgen receptor (AR) mutations in men with metastatic castration-resistant prostate cancer (mCRPC): Incidence and natural history.
Authors: Bernard-Tessier Alice , Mulier Guillaume , Nay Paula , Baldini Capucine , Albiges Laurence , Colomba Emeline , Flippot Ronan , Lavaud Pernelle , Naoun Natacha , Patrikidou Anna , Loriot Yohann , Massard Christophe , Foulon Stéphanie , Fizazi Karim
Published: March 2023

221

Background: AR ligand binding domain (LBD) activating somatic point mutation is a known mechanism of resistance to androgen-receptor signaling inhibitor (ARSI) treatment in mCRPC, leading to a persistent addiction to steroid hormones. Two early phase trials investigating CYP11A1 inhibitors - CYPIDES (ODM208, NCT03436485) and STESIDES (ODM209, NCT03878823) - recruited mCRPC patients with and without pre-specified AR LBD mutation. In CYPIDES Part 1, AR LBD mutations (ARm) strongly predicted for PSA decline with ODM-208 (Fizazi, ASCO GU 2021). Here, we evaluated clinical and genomic data associated with ARm in patients with mCRPC. Methods: We reviewed clinical and molecular data from patients with mCRPC who progressed after ≥1 ARSI and ≥1 line of taxane-based chemotherapy or were ineligible to chemotherapy, pre-screened in CYPIDES and STESIDES trials at our center. Circulating tumor DNA (ctDNA) was tested for AR LBD mutation (Guardant360 CDx and Sysmex OncoBEAM) and for genomic analysis (FoundationOne Liquid CDx, STING trial, NCT04932525) to screen for actionable targets. Results: From March 2020 to January 2022, 272 men were screened. Median age was 62y. Overall, 212 (78%), 202 (74%), and 240 (88%) patients had received previous abiraterone, enzalutamide, and docetaxel respectively. Median PSA at screening was 59 ng/mL (IQR 11; 246). ARm was found in 69 patients (25%). The most frequent mutations were L702H (15%), T878A (12%), H875Y (7%), V716M (2%), F877L (2%), W742C (1%), globally consistent with previous reports. Associations of ARm with relevant baseline characteristics of patients are summarized. Duration of enzalutamide exposure was correlated with the number of AR mutations per patient (p = 0.006) whereas no correlation was found for abiraterone exposure duration (p=0.71). In 173 (64%) patients with available genomic testing, no alterations were found to be mutually exclusive with ARm, including in DNA repair alteration. Conclusions: AR LBD mutations were detected in ctDNA in 25% of men with advanced mCRPC treated with at least one ARSI. Their incidence was associated with a longer duration of treatment with enzalutamide and a longer time from CRPC and prostate cancer diagnosis. [Table: see text]