bluuebunny/crossref_metadata_2025 huggingface dataset:
Psychometric evaluation and adaptation of the stigma affiliation scale into the Indonesian language in primary family caregivers of schizophrenia patients
Authors: Kurnianingsih Tuti , Lumbantoruan Patricia Beta Ayu , Afriandi Irvan , Pandia Veranita , Dhamayanti Meita
Published: January 2024

Introduction

The Stigma Affiliation Scale (ASS) is an instrument to assess affiliation stigma used widely worldwide. This study aims to adapt the ASS to the Indonesian language and to evaluate the psychometric properties of the ASS among family caregivers of people with schizophrenia in Indonesia.

Methods

A cross-sectional study was conducted of 94 schizophrenia patients’ family caregivers in communities, i.e., an items analysis, construct validity using the known-group method, and internal consistency reliability.

Results

The consistency between items and overall scores using Pearson product-moment correlation shows that all the items had Pearson’s coefficient correlation ≥ 0.300, indicating good and acceptable discriminant power. The construct validity using the Mann–Whitney U test comparing the ASS scores between the primary caregivers and other family members of schizophrenic patients showed higher scores in the primary caregivers than the other family members in the three domains (p < 0.0001), indicating excellent construct validity. Cronbach’s alpha was 0.80–0.89 and above 0.90, which indicate good and excellent reliability, respectively.

Conclusion

The Indonesian version of ASS shows good psychometric properties among family caregivers of people with schizophrenia in Indonesia.
PD-L1 expression and its significance in advanced NSCLC: real-world experience from a tertiary care center
Authors: Kilaru Sindhu , Panda Soumya Surath , Moharana Lalatendu , Mohapatra Debahuti , Mohapatra Satya Sundar G. , Panda Adyakinkar , Kolluri Spoorthy , Devaraj Suma , Biswas Ghanashyam
Published: January 2024

Background

Targeted therapies against programmed death ligand-1 (PD-L1) in non-small cell lung cancer (NSCLC) have revolutionized the management in recent years. There is paucity of data on the significance of PD-L1 expression in NSCLC from India. We aimed to study the prevalence of PD-L1 expression and its relation with different clinico-pathological parameters in advanced NSCLC from a tertiary care center in Eastern India.

Methods

All consecutive patients with advanced NSCLC diagnosed from January 2020 to December 2021 were prospectively evaluated for PD-L1 expression in formalin fixed-paraffin embedded tumor tissue specimens using immunohistochemistry analysis. A PD-L1 expression of < 1%, 1–49%, and ≥ 50% were considered negative, low, and high expression positive respectively, and association with various parameters was performed.

Results

Out of the 94 patients (mean age 59.6 ± 14 years and 63.8% males), PD-L1 positivity was seen in 42 (44.7%) patients, with low positivity (1–49%) in 29 patients and high positivity (≥ 50%) in 13 patients. Epidermal Growth Factor Receptor (EGFR) mutations were seen in 28 patients (29.8%). There were no significant differences in PD-L1 positivity with respect to gender, age, and molecular mutation status. PD-L1 positivity was significantly associated with tobacco use (p = 0.04), advanced tumor stage (p < 0.001), and higher nodal stage (p < 0.001). Median overall survival in the cohort was 17 months and it was not significantly different between the PD-L1 positive and negative groups.

Conclusions

Forty-five percent of advanced NSCLC patients in our cohort showed positive PD-L1 expression and it is associated with tobacco use and aggressive tumor characteristics.
Second-stage pipeline embolization device treatment with coil embolization for large cerebral aneurysm prevents silent diffusion-weighted image ischemic infarction: a retrospective study
Authors: Kawamura Yosuke , Takigawa Tomoji , Nariai Yasuhiko , Hyodo Akio , Suzuki Kensuke
Published: January 2024

Background

Second-stage flow diversion with coil embolization may improve occlusion outcomes and reduce periprocedural complications in patients with cerebral aneurysm. However, the actual cause behind this is unclear. In this study, we aimed to compare the efficacy and safety of second-stage pipeline embolization device (PED) and single-stage PED with coil embolization.

Results

Of the 22 treated patients with aneurysm, 10 and 12 were treated with second-stage PED and single-stage PED with coil embolization, respectively. The mean follow-up duration was 29.6 months. The mean numbers of diffusion-weighted image (DWI)-positive spots on day 1 post-procedure were 4.9 and 10.8 in the second-stage and single-stage PED with coil embolization groups, respectively (P = 0.01). Deterioration of the modified Rankin scale score was not ≥ 2 in any patient during follow-up in the second-stage PED group but was observed in 16.7% of cases (2/12) in the single-stage PED with coil embolization group (P = 0.48). On follow-up angiography, complete occlusion was observed in all patients (10/10) in the second-stage PED group and 66.7% (8/12) in the single-stage PED with coil embolization group (P = 0.09).

Conclusions

The second-stage PED strategy significantly reduces the number of DWI high-intensity spots, leading to the prevention of ischemic complications. This strategy may help to prevent complications and reduce morbidity.
Comparison of four DNA barcoding loci to distinguish between some Apiaceae family species
Authors: Abdelaziz Shaimaa A. , Khaled Khaled A. M. , Younis Rania A. A. , Al-Kordy Magdy A. , El-Domyati Fotouh M. , Moghazee Mona M.
Published: January 2024

Background

The Apiaceae family is among the most significant plant families because it contains both beneficial and poisonous plants. Due to their morphological similarity, these harmless and lethal species are frequently confounded. Cumin, fennel, and anise are the most prevalent members of the family Apiaceae in Egypt. Members of this family are routinely used as medical surrogates, so it is crucial that they are correctly identified and distinguished. DNA barcoding is a molecular technique used for identifying species and reconstructing phylogenetic trees.

Results

Six plants from this family were chosen for this study due to their medicinal importance, and four DNA barcoding loci (rbcL, matK, trnH-psaA, and ITS) were used to identify them. The amplicons were sequenced, and the comparative analysis was conducted between the sequences evaluated and the most significant Blast results. The DNA rbcL, trnH-psaA, and ITS barcodes exhibited similar amplicons among the six species of Apiaceae, while the trnH-psaA barcode exhibited different amplicons among the Apiaceae. Maximum likelihood approach was used to calculate the genetic distance between the sex species of Apiaceae. The most significant findings were that the one from four DNA barcoding was able to distinguish between distinct species and confirm their evolutionary belonging to this family.

Conclusions

The current study concludes that trnH-psbA and ITS DNA identifiers can be used to accurately identify, differentiate, and record Apiaceae species, while the rbcl DNA barcode appears to have fallen short of its intended purpose. So, the data that come from DNA barcodes could be used for the biodiversity assessment and the similarities between hazardous and commercial plants to resolve some of these deficiencies.
RcMYB8 enhances salt and drought tolerance in rose (Rosa chinensis) by modulating RcPR5/1 and RcP5CS1
Authors: Zhang Yichang , Yu Shuang , Niu Pengfei , Su Lin , Jiao Xuecheng , Sui Xiuyu , Shi Yaru , Liu Boda , Lu Wanpei , Zhu Hong , Jiang Xinqiang
Published: January 2024

Plant Myeloblastosis (MYB) proteins function crucially roles upon variegated abiotic stresses. Nonetheless, their effects and mechanisms in rose (Rosa chinensis) are not fully clarified. In this study, we characterized the effects of rose RcMYB8 under salt and drought tolerances. For induction of the RcMYB8 expression, NaCl and drought stress treatment were adopted. Rose plants overexpressing RcMYB8 displayed enhanced tolerance to salinity and drought stress, while silencing RcMYB8 resulted in decreased tolerance, as evidenced by lowered intra-leaf electrolyte leakage and callose deposition, as well as photosynthetic sustainment under stressed conditions. Here, we further show that RcMYB8 binds similarly to the promoters of RcPR5/1 and RcP5C51 in vivo and in vitro. Inhibiting RcP5CS1 by virus-induced gene silencing led to decreased drought tolerance through the reactive oxygen species (ROS) homeostatic regulation. RcP5CS1-silenced plants showed an increase in ion leakage and reduce of proline content, together with the content of malondialdehyde (MDA) increased, lowered activities of Catalase (CAT), peroxidase (POD) and superoxide dismutase (SOD). Our study highlights the transcriptional modulator role of RcMYB8 in drought and salinity tolerances, which bridges RcPR5/1 and RcP5CS1 by promoting ROS scavenging. Besides, it is probably applicable to the rose plant engineering for enhancing their abiotic stress tolerances.

Graphical Abstract
Automatic multi-disease classification on retinal images using multilevel glowworm swarm convolutional neural network
Authors: Chavan Rupali , Pete Dnyandeo
Published: January 2024

In ophthalmology, early fundus screening is an economical and effective way to prevent blindness from eye diseases. Because clinical evidence does not exist, manual detection is time-consuming and may cause the situation to be delayed clinically. With the development of deep learning, a wide variety of eye diseases have shown promising results; however, most of these studies focus on only one disease. Therefore, focusing on multi-disease classification based on fundus images is an effective approach. Consequently, this paper presents a method based on the multilevel glowworm swarm optimization convolutional neural network (MGSCNN) for the classification of multiple diseases. It is proposed that the proposed system has two stages, namely preprocessing and classification. In the beginning, the images are normalized, smoothed, and resized to prepare them for preprocessing. After pre-processing, the images are fed to the MGSCNN classifier to classify an image as normal or abnormal (covering 39 different types of diseases). In the CNN classifier, with the help of Glowworm Swarm Optimizer (GSO), we optimally detect the structure and hyperparameters of CNN simultaneously. This approach achieves an excellent accuracy of 95.09% based on various metrics.
Immune-related adverse event in the emergency department: methodology of the immune-related emergency disposition index (IrEDi)
Authors: Reyes-Gibby Cielito C. , Caterino Jeffrey M. , Coyne Christopher J. , Kyriacou Demetrios N. , Qdaisat Aiham , McQuade Jennifer , Owen Dwight H. , Bischof Jason J. , Shete Sanjay , Yeung Sai-Ching Jim
Published: January 2024

For many cancer patients, immune checkpoint inhibitors (ICIs) can be life-saving. However, the immune-related adverse events (irAEs) from ICIs can be debilitating and can quickly become severe or even be fatal. Often, irAEs will precipitate visits to the emergency department (ED). Therefore, early recognition and the decision to admit, observe, or discharge these patients from the ED can be key to a cancer patient’s morbidity and mortality. ED clinicians typically make their decision for disposition (admit, observe, or discharge) within 2–6 h from their patient’s ED presentation. However, irAEs are particularly challenging in the ED because of atypical presentations, the absence of classic symptoms, the delayed availability of diagnostic tests during the ED encounter, and the fast pace in the ED setting. At present, there is no single sufficiently large ED data source with clinical, biological, laboratory, and imaging data that will allow for the development of a tool that will guide early recognition and appropriate ED disposition of patients with potential irAEs. We describe an ongoing federally funded project that aims to develop an immune-related emergency disposition index (IrEDi). The project capitalizes on a multi-site collaboration among 4 members of the Comprehensive Oncologic Emergency Research Network (CONCERN): MD Anderson Cancer Center, Ohio State University, Northwestern University, and University of California San Diego. If the aims are achieved, the IrEDi will be the first risk stratification tool derived from a large racial/ethnically and geographically diverse population of cancer patients. The future goal is to validate irEDi in general EDs to improve emergency care of cancer patients on ICIs.
Pulmonary wedge resection for lung cancer developing in a single transplanted lung: a case report
Authors: Aze Koji , Sato Masaaki , Nagano Masaaki , Nakajima Jun
Published: January 2024

Background

Primary lung cancer arising in a transplanted lung is much rarer than cancer arising in a native lung. We herein describe a case of lung cancer developing in a transplanted lung after single-lung transplantation. Wedge resection was safely and successfully completed using venovenous extracorporeal membrane oxygenation (VV-ECMO).

Case presentation

A 63-year-old man underwent right single-lung transplantation for idiopathic interstitial pneumonia from a donor in his 60s with a 44-pack-year history of smoking. One year 6 months later, computed tomography revealed a 10-mm nodule in the right lower lobe of the transplanted lung. Fluorodeoxyglucose-positron emission tomography showed abnormal accumulation of fluorodeoxyglucose (maximum standardized uptake value, 2.8) in the same area, suggesting lung cancer. However, percutaneous or transbronchial biopsy was technically impossible. Surgical diagnosis and treatment were planned, and VV-ECMO was introduced before wedge resection. Although pleural adhesion and the location of the nodule close to the hilum resulted in a challenging procedure, the operation was completed in 190 min. The final pathological diagnosis was papillary adenocarcinoma.

Conclusions

Lung cancer arising in a lung transplanted from a brain-dead donor is rare. Limited lung resection using VV-ECMO is considered a useful option, particularly in cases of single-lung transplantation.
Days spent with healthcare contact by patients with metastatic castrate-resistant prostate cancer in the last year of life.
Authors: Sentana Lledo Daniel , Barnett Amelia , Einstein David Johnson , Gupta Arjun , Morgans Alicia K.
Published: January 2024

100

Background: Days spent with healthcare contact while pursuing cancer treatment (i.e., “time toxicity”) may be particularly relevant when life expectancy is most limited. Patients with metastatic castrate resistant prostate cancer (mCRPC) ultimately choose whether to pursue further cancer directed therapies or receive supportive care and reduce expected healthcare contact. We sought to define the evolution of time toxicity over the last year of life in patients with mCRPC. Methods: Contact days, defined as any day with healthcare contact outside the home, were retrospectively assessed and categorized (e.g., infusion, ER visit) in 96 patients at an academic cancer center. The primary objective was to compare contact days in the 90-day period between 12 and 9 months prior to date of death (“first quarter”) and the 90-day period prior to death (“last quarter”) using the Wilcoxon signed rank test. Additional exploratory analyses were performed evaluating the association between clinicodemographic variables and systemic treatments received. Results: There were higher median [IQR] total contact days in the last quarter (6 [2,17]) compared to the first quarter (4 [3,6], p < 0.01), driven by ER visits and hospitalizations. Compared to patients off treatment/supportive care (4 [3,4]) in the first quarter, chemotherapy (5 [4,6], p = 0.02) and radiotherapeutics (5 [4,9], p = 0.03) were associated with greater contact days, but androgen signaling inhibitors were not (3 [2,5], p = 0.20). However, there were no significant differences in contact days between any treatment vs non-treatment in the last quarter. Non-White patients (n = 27) and those without higher education (n = 30) had more contact days in the last quarter (9 [2,19], p < 0.01 for both). Patients who enrolled on hospice 7 days (n = 11) or 30 days (n = 39) before date of death had more contact days in the last quarter than those with earlier enrollment (23 [7,28], p < 0.01; 13 [4,24], p < 0.01 respectively). Conclusions: Healthcare contact was higher in the last 3 months of life due to increased number of days with inpatient level of care. Further studies to define healthcare exposure and time toxicity of mCRPC treatments are warranted to inform patient expectations towards the end-of-life. [Table: see text]
PRO-WAVE1: Monitoring patient reported outcomes (PROs) in prostate cancer through Wave Health, a novel ePRO health platform.
Authors: Cacho Diego , Congregado Belen , Rivero Belenchon Ines , Linares Espinos Estefania , Basterretxea Laura , Sancho Gemma , Lainez Nuria , Buchser David , Sanguedolce Francesco , Gurruchaga Ibon , Gomez Mediavilla Borja , Esteban Brigida , Hernandez Amaia , Lashey Matthew , Duran Ignacio
Published: January 2024

114

Background: It is well established that the monitoring and evaluation of PROs in cancer patients has a positive impact in both quality of life and overall survival.1 In parallel, the widespread use of electronic devices such as smart phones in the general population have increased significantly over recent years,2 representing a unique opportunity to operationalize ePROs. However, there is uncertainty about the feasibility and applicability of these technologies in certain patient population such as prostate cancer (PC) patients. PRO-WAVE1 aims to determine the acceptability and engagement of the Wave Health patient app and healthcare provider portal, enhanced for PC patients. Specific endpoints include measuring longitudinal use of varying ePROs to impact care management, patient health literacy, and ability to identify and manage emerging risks. Methods: The study is underway across eight sites in Spain. Patient ePRO engagement is being evaluated through the administration of 19 ePRO questionnaires over the course of 13 weeks, including: health-related QoL (FACT-P); health literacy (CHLT-30-Dkspa); and weekly reviews of symptoms (WSR). Compliance rates per patient and per cohort will be reported at assessment time-points and for the entire study period. Secondary objectives evaluated include engagement with Wave Health App; changes in HRQoL; changes in health literacy; and the perceived value of the platform by patients and HCPs. Results: 98 patients were enrolled in the study. Patient cohort representation included: 44.9% mHSPC, 36.7% mCRPC, and 18.3% nmPC. Of the 98 patients, 84 successfully became active in the study and participated (85.7% acceptance). As of September 20, 2023, among the completed patients (N=46), the compliance rate for the ePRO questionnaires was 93.7%. During their participation, these patients used the app for an average of 12.2 weeks, and approximately two-thirds (67.4%) used the app for all 13 weeks. Weekly “usefulness” ratings among the HCPS averaged 3.6 (scale: 1 “not at all useful” to 5 “very useful”). Conclusions: Study results exceeded expectations for patient acceptability and engagement with the app; as well as perceived usefulness of the portal among HCPs – suggesting the platform as an impactful tool for patients working with HCPs to manage treatment journeys. A larger study using a comparator arm will help further evaluate the impact on costs and clinical outcomes. 1. Basch E., JAMA 2017. 2. Statista, 2023.
Outcomes of elderly patients (pts) treated with docetaxel (DOC) for metastatic castration-sensitive prostate cancer (mCSPC): Results from ECHOS, a multicenter Italian observational study.
Authors: Caffo Orazio , Maruzzo Marco , Pravisano Federico , ButtIgliero Consuelo , Sorarù Mariella , Masini Cristina , Gori Stefania , Sabbatini Roberto , Pappalardo Annalisa , Cattrini Carlo , Fornarini Giuseppe , Vittimberga Isabella , Rametta Alessandro , Zucali Paolo Andrea , Fantinel Emanuela , Grillone Francesco , Fratino Lucia , Galli Luca , Giordano Monica , Basso Umberto ,   on behalf of ECHOS trial group
Published: January 2024

153

Background: ECHOS trial is a large real-world study which is collecting data on mCSPC patients treated in the daily clinical practice in Italy from 2015. To date, > 1500 pts were included in the study, most of them treated with DOC, according to the availability of the active agents over the time in Italy. In the present analysis, we assessed the outcomes of pts ≥75 yrs old who received DOC for mCSPC. Methods: We retrospectively and prospectively reviewed the clinical records of a consecutive series of mCSPC pts treated with DOC in the daily clinical practice in 69 Italian Hospitals. The treatment mostly consisted of DOC at the standard dose of 75 mg/sqm every 3 wks for six courses. For each pt we recorded the pre and post-DOC clinical history, the baseline characteristics of the pts, the treatment details and clinical outcomes. For the purpose of the present study, we considered only pts who ended chemotherapy by September 2022. Results: Among 920 mCSPC pts treated with DOC, 132 (14.4%) were ≥ 75 yrs old. Most of them (76%) presented de novo disease with high-volume features. Their baseline characteristics were similar to those of younger pts excepting for baseline hemoglobin levels which were significantly lower in older pts (median 12.6 vs 13.5; p = 0.001). Older pts received either a reduced dose (16.7%) or a modified schedule (8.4%) more frequently than younger one (p < 0.0001). Thirty-six pts experienced a grade 3-4 toxicity, which was mainly hematological (75% of the cases). The median progression-free survival (PFS) was 12.6 mos in older pts compared to 14.9 mos observed in younger ones (p 0.2). The median number of life prolonging agents administered after DOC progression was 1 in pts ≥75 yrs as well as in pts < 75 yrs. The median overall survival (OS) was 27.9 mos and 42.4 mos in older and younger pts, respectively (p < 0.0001). Conclusions: Our data suggest that DOC was efficacious and well-tolerated in mCSPC pts ≥75 yrs although the treatment was administered with either dose or schedule modifications in about 25% of the cases. No differences were observed in terms of PFS between pts ≥75 and ones < 75 yrs. Nevertheless, the median OS of older pts was significantly worse compared to that of younger ones.
Novel dual inhibitors of AR/AR variants and AKR1C3: Preclinical activities for advanced prostate cancer therapy.
Authors: Gao Allen , Ning Shu , Armstrong Cameron , Xing Enming , Lou Wei , Li Pui-Kai , Evans Christopher P.
Published: January 2024

169

Background: AR/AR-variants and AKR1C3 play critical roles in prostate cancer progression and driving resistance to antiandrogens, and are attractive targets for therapeutic intervention for advanced prostate cancer. However, there are currently no clinically available therapies that simultaneously target both AR/AR variants and AKR1C3. We have developed the novel small molecule inhibitors, LX-1 and its analog LX-1S, which target both the AR-V7 splice variant and the enzyme AKR1C3. Methods: A library of the LX compounds was designed and synthesized according to structure based computer modeling. The effects of the lead LXs on the expression and activity of AR/AR-variants and AKR1C3 were evaluated. RNA-seq was performed on the lead LXs. Resistant cell sublines generated from C4-2B cells resistant to enzalutamide (MDVR), apalutamide (ApalR), darolutamide (DaroR), or abiraterone (AbiR) were treated with LX-1 or their respective antiandrogen. Mice bearing VCaP xenograft tumors and LuCaP35CR PDX tumors were treated with LX-1/LX-1s and effects on tumor growth were assessed. Results: Molecular docking studies and in vitro experiments demonstrated that LX compounds effectively bind to the AKR1C3 active site and inhibit AKR1C3 enzymatic activity. LX compounds were also shown to reduce AR/AR-V7 expression and inhibit their target gene signaling, induce G0/G1 arrest in anti-androgen resistant cell lines. LX-1/LX-1S treatment resulted in reduced tumor volumes and decreased intratumoral testosterone in both xenograft tumor and PDX models. LX-1 effectively inhibited the conversion of androstenedione into testosterone in tumor-based ex vivo enzyme assays. Moreover, LX-1 synergized with enzalutamide and abiraterone as well as docetaxel, suggesting its potential to enhance the anti-tumor activity of these standard therapies in resistant prostate cancer. Furthermore, LX-1/LX-1S improved enzalutamide treatment in resistant prostate cancer tumor models. Notably, LX-1S demonstrates significantly better bioavailability and efficacy than LX-1 in reducing resistant cell growth in both in vitro and in vivo animal models. Conclusions: Our study unveils the potential of LX compounds, especially LX-1 and its analog LX-1S, as promising therapeutic agents for advanced prostate cancer. These compounds not only inhibit AR and AKR1C3 signaling but also suppress resistant tumor growth and synergize with antiandrogens to enhance their therapeutic efficacy.
Outcomes for patients with mCRPC and liver metastasis receiving 177-Lu-PSMA-617 treatment.
Authors: Muniz Miguel , Sartor A. Oliver , Mahmoud Ahmed M. , Orme Jacob , Kwon John Y. , Andrews Jack R. , Kase Adam McLain , Mosalem Osama M , Bryce Alan Haruo , Riaz Irbaz Bin , Thorpe Matthew , Kendi Ayse T. , Johnson Geoffrey , Ravi Praful , Kwon Eugene D. , Childs Daniel S
Published: January 2024

175

Background: It is well-known that patients with liver metastases from metastatic castration resistant prostate cancer (mCRPC) have poorer or transient responses to many forms of systemic therapy. Data on outcomes following treatment with Lutetium-177–PSMA-617 is scarce. The VISION trial reports hazard ratios for overall survival in the subgroup of patients with liver metastases without disclosing the absolute duration of survival. Using real-world clinical data, we examine this important subgroup of patients, describing their PSA response rates and survival. Methods: A single institution database was assembled to include all patients receiving 177-Lu-PSMA-617 at Mayo Clinic Rochester, MN, and starting treatment in the interval of March 2022 to March 2023. Baseline clinicopathologic and imaging characteristics were abstracted. Patients were categorized based on the presence or absence of measurable liver metastases on their baseline PSMA PET scan. Best PSA response while on treatment was annotated and reported as percent decline from baseline. Survival was calculated from date of first cycle of 177-Lu-PSMA-617. PSA50 response and overall survival (OS) outcomes for the two groups (liver metastases versus no liver metastases) were compared using Chi square test and Kaplan-Meier method, respectively. Those with available pre-treatment circulating tumor DNA (ctDNA) genomic profiling, performed by Guardant (83 gene panel), were assessed for the presence of pathogenic and likely pathogenic alterations. Findings are summarized using descriptive statistics. Results: The overall cohort consisted of 212 patients, including 29 (14%) with liver metastases on pre-treatment PSMA PET/CT. The median number of cycles received was 4 (range, 1-6) for patients with liver metastases and 6 (range, 1-6) for those without hepatic involvement. The observed PSA50 response trended lower for those with liver metastases (34.5% [10/29] versus 51% [94/183], p= 0.091). At median (IQR) follow-up of 10 (8-12) months, there was a numerical but not statistically significant difference in median OS (11.28 months versus NR, p=0.066). In the exploratory analysis of baseline ctDNA, BRCA2 copy number loss was relatively enriched among patients with liver metastases (4 of 19, 21%) versus patients without liver disease (5.7%, 9/158). Conclusions: Our data suggest that the presence of liver metastases predict poorer outcomes in patients receiving Lutetium-177–PSMA-617 treatment, which is similar to data reported with other forms of systemic therapy for mCRPC. To maximize the anti-tumor activity of radioligand therapy in the liver, combination approaches should be explored.
Men with adrenal-permissive HSD3B1 genotype and prostate cancer mortality: Results from the Veterans Affairs Health System Million Veteran Program.
Authors: McKay Rana R. , Nelson Tyler J. , Pagadala Meghana , Teerlink Craig , Gao Anthony , Bryant Alex , Agiri Fatai , Guram Kripa , Pridgen Kathryn , Seibert Tyler M , Lee Kyung Min , Carter Hannah , Lynch Julie Ann , Hauger Richard , Rose Brent S.
Published: January 2024

207

Background: The 3β-HSD1 protein, encoded by the HSD3B1 gene, catalyzes the rate-limiting step necessary of non-testicular testosterone and dihydrotestosterone production. The common adrenal-permissive HSD3B1(1245C) allele is responsible for encoding 3β-HSD1 protein with decreased susceptibility to degradation resulting in increased of extragonadal androgen synthesis. Retrospective studies have suggested an association with the HSD3B1 CC genotype and resistance in prostate cancer. Methods: We conducted a cohort analysis of patients with a diagnosis of prostate cancer enrolled in the Million Veteran Program with genotyping and phenotyping information available through Veterans Health Administration. The primary endpoint was to evaluate prostate cancer-specific mortality (PCSM) in the overall cohort. PCSM was defined as the time from diagnosis to death from prostate cancer, censored at the date of last VA follow-up. Secondary endpoints included incidence of metastases and PCSM in predefined subgroups. HSD3B1 genotype status was categorized as AA (wild type), AC (heterozygous), CC (homozygous). Results: The study included 5287 men with prostate cancer; 402 (7.6%) HSD3B1 CC, 1970 (37.3%) HSD3B1 AC, and 2915 (55.1%) HSD3B1 AA. The cohort included 29.6% (n=1567) Black men of whom 1.2% (n=19) were HSD3B1 CC. Cumulative incidence of PCSM at five years after prostate cancer diagnosis was higher among men homozygote for HSD3B1 variant genotype CC compared to heterozygotes AC and wild-type homozygotes AA (1.9% for AA vs. 2.1% for AC vs. 4.0% for CC, p<0.017). While the cumulative incidence of metastases was similar in between HSD3B1 genotype groups (12.3% for AA, 11.8% for AC, 13.2% for CC, p=0.789), in patients who developed metastatic disease (n=619), the cumulative incidence of PCSM at five years was higher in the HSD3B1 CC group compared to AC and CC (19.2% for AA vs. 17.6% for AC vs. 37.3% for CC, p<0.005). Conclusions: Among men with prostate cancer, HSD3B1 CC genotype is associated with inferior outcomes. The HSD3B1 biomarker may help identify patients who may benefit from therapeutic targeting of 3β-HSD1 and the androgen-signaling axis.
11-Ketotestosterone and time to castration resistance in patients with recurrent non-metastatic prostate cancer receiving androgen deprivation therapy.
Authors: Guillemette Chantal , Dahmani Cylia , Caron Patrick , Simonyan David , Lacombe Louis , Aprikian Armen G. , Saad Fred , Carmel Michel , Chevalier Simone , Levesque Eric
Published: January 2024

209

Background: The contribution of 11-oxygenated androgens to disease progression in men receiving androgen deprivation therapy (ADT) for recurrent non-metastatic prostate cancer (PCa) remains unresolved. We hypothesized that evaluating circulating levels of 11-oxygenated androgens, such as the potent androgen receptor (AR) agonist 11-ketotestosterone (11KT), could serve as a potential predictor for the onset of castration resistance (CRPC). Methods: The multi-institutional prospective PROCURE cohort involves 2,026 patients who underwent radical prostatectomy for localized PCa. In this cohort, a subset of 145 patients who received ADT therapy for recurrent disease and had available plasma samples post-surgery were included in this study. The effect of therapy on steroid levels was assessed in paired samples obtained before and after the initiation of ADT (n=50), and samples from patients under combined ADT with AR pathway inhibitors, enzalutamide (n=10) and abiraterone (n =15). 11-oxygenated androgens (n=7) and canonical steroids, such as testosterone (T) and dihydrotestosterone (DHT), were quantified by mass spectrometry. Kaplan-Meier survival analyses were used to investigate relationships of androgen levels with the occurrence of CRPC. Results: 11-oxygenated androgens remained unaffected by ADT, which stands in contrast to the observed changes in T, DHT and other steroids. In men with castrated T levels, 11KT was the most abundant androgen. Elevated 11KT was associated with a sooner time to CRPC ( P=0.023). The 10-year CRPC event-free rate was 63% vs. 84% for 11KT levels above and below the median, respectively. The initiation of enzalutamide had no impact on 11-oxygenated androgen levels, whereas abiraterone significantly reduced 11KT levels owing to the adrenal origin of its precursor. Conclusions: Our findings indicate that 11KT is a significant component of the hormonal profile predictive of an earlier onset of CRPC and inhibition of its production by the CYP17A1 inhibitor abiraterone.
Estimating median overall survival of apalutamide compared to placebo in metastatic hormone-sensitive prostate cancer (mHSPC) populations: Statistical extrapolations of the TITAN study.
Authors: Agarwal Neeraj , Bjartell Anders , Juárez Álvaro , Kerßenboom Ronja , Perualila Nolen , Wigfield Peter , Chi Kim N.
Published: January 2024

223

Background: Apalutamide plus ADT (APA) demonstrated significantly improved overall survival (OS) compared to placebo plus ADT (PBO) for patients with mHSPC in the TITAN study (HR, 0.65; 95% CI, 0.53 to 0.79; P < .0001). At the time of final analysis, the median OS was not reached in the APA arm or subgroups after a median follow up of 44 months. This work aimed to estimate OS medians for APA and PBO arms beyond the TITAN follow-up by fitting validated survival models. Methods: OS was predicted for the overall population treated with APA or PBO, with or without Inverse probability of censoring weighting (IPCW) crossover adjustment, and for the low and high-volume (LVD, HVD), HVD synchronous and HVD metachronous subgroups. General population mortality adjusted TITAN patient-level data was fitted to six parametric models (Weibull, exponential, log-normal, log-logistic, generalized gamma, and Gompertz) using the individual fits approach. Best fit was determined by statistical and visual fits, along with the Akaike Information Criterion (AIC)/Bayesian Information Criterion (BIC) ranking, according to the recommendations of the National Institute for Health and Care Excellence Decision Support Unit 14. Results: Best fit extrapolation estimated median OS of 71.8 months for the overall mHSPC population treated with APA (Table), leading to an estimated median improvement of up to 32 months versus PBO. Median OS values predicted by the other five models ranged from 62.4 to 78.1 months. Across subgroups, best fit models estimated median OS of 113.7 months for APA in LVD and a consistent median OS of 52 months for HVD subgroups. Conclusions: While results of this extrapolation study should not be equated to those of a clinical trial, this analysis meets an evidence gap by predicting median OS in the APA arm of the TITAN study for the overall mHSPC population as well as for various subgroups of this heterogeneous population, strengthening the evidence supporting early treatment with APA across the broad mHSPC population. [Table: see text]
A novel blood-based mRNA genomic test for screening, early detection, prognosis, and monitoring of prostate cancer: A multicenter study.
Authors: Hashimoto Yutaka , Verma Shiv , Deng Guoren , Chauhan Dharam P , Nair Sujit , Yoshino Hirofumi , Arima Junya , Liu Yutong , Hatano Koji , Shivakumar Yogesh , Krishnappa Raghunath S. , Chandran Chitra , Ragavan Narasimhan , Enokida Hideki , Nonomura Norio , Balaji K C , Rawal Sudhir K , Tewari Ashutosh K. , Dahiya Rajvir , Gupta Sanjay
Published: January 2024

271

Background: Current screening tools, including prostate-specific antigen (PSA) and clinicopathologic parameters, have limitations in the diagnosis and prognosis of prostate cancer. This study examined whether genomic biomarkers can improve screening and monitoring of prostate cancer. Methods: We identified a panel of 25 prostate cancer-related genes through rigorous bioinformatics, computational analyses and genetic testing. These tests, developed by Geneverify Inc. (Hayward, CA; U.S. patent # 10801072 and 10822661) were utilized and optimized by qRT-PCR to determine the diagnostic and prognostic ability of prostate cancer using blood and tissues. The log2-fold increase in gene expression was used to assign the risk score to individual patients. ROC (receiver operator characteristic), AUC (area under ROC curve), and calibration curves were generated to display the overall performance and discrimination ability to separate cancer and non-cancer specimens. Results: A total of 419 prostate cancer patients (135 blood and 284 tissue samples) and 130 normal samples were analyzed in this study. The eligibility criteria were to collect blood and surgical specimens from patients with prostate cancer from 9 hospitals. The study endpoints were to analyze mRNA genomic profiling and correlate with clinicopathologic parameters of the patients. In the blood, a 25-panel gene-set separated prostate cancer patients (n=135) from non-cancer (n=30), AUC = 0.906 [sensitivity = 90% and specificity = 91%]. Assessment of tissue specimens from benign (n=100) and cancer patients (n=284) showed similar results with AUC = 0.9514 [sensitivity = 95% and specificity = 94%]. Interestingly, patients with Gleason grades (GS) >7 showed higher expression of these genes compared to GS <7, suggesting the prognostic ability of the gene-set. When we compared the gene expression in blood verses tissues, there were similar patterns, suggesting that blood can be used for screening, diagnosis and risk assessment of prostate cancer. Conclusions: To our knowledge, this is the first study to investigate the role of mRNA-based genomic signatures for screening, early diagnosis and prognosis of prostate cancer using blood samples. Our data suggest that blood mRNA-genomic profiling developed by Geneverify has the ability to diagnose prostate cancer and stratify patients into distinct prognostic groups, which in turn help in making better treatment strategies.
A novel cardiovascular disease risk score for prediction of atherosclerotic disease events in men with prostate cancer.
Authors: Stabellini Nickolas , Tan Min Choon , Cullen Jennifer , Weintraub Neal L , Shanahan John , Agarwal Neeraj , Patel Sagar A. , Montero Alberto J. , Guha Avirup
Published: January 2024

314

Background: Prostate cancer patients (PC) face an elevated risk of both developing atherosclerotic cardiovascular disease (ASCVD). The American College of Cardiology Pooled Cohort Equations (PCE) for ASCVD predictions may lack accuracy. Methods: Males ≥18 years, diagnosed with PC between 2005-2012 at a hybrid academic-community practice were included. Using XGBoost algorithm we developed using a training subset of the cohort (50% train + 25% test), ranked 33 covariates (including demographic, treatment-related and social determinants of health (SDOH) information) for ASCVD prediction using SHAP (Shapley additive explanations) values. The top 10 predictors were transformed in a predictive equation using logistic regression models. This equation was tested in the cohort validation subset (25%), and subsequently compared to the PCE risk score. Results: We included 1,506 patients, with a median age of 67 (IQR 60-74) years, 13.8% had advanced stage disease (TNM III-IV), 1.5% had high risk PC (Gleason 8-10), and 20.5% received androgen deprivation therapy (ADT). Of those, 10.4% had a 10-year ASCVD risk. The PCE had an area under the curve (AUC)=0.61 and underestimated ASCVD in 0.9% (mean risk=20.1% [95% CI 17.2-23.0] vs. mean predicted risk=19.2% [95% CI 18.6-19.8]). The equation pooled from the top-10 predictors of the ML algorithm (C-index=0.78 [95% CI 0.75-0.81]) achieved an AUC=0.71 (Table). Conclusions: Conventional PCE tend to underestimate ASCVD risk in males with PC. A cancer-specific model inclusive of SDOH exhibits good performance for predicting ASCVD risk in this population. [Table: see text]
Post radical prostatectomy (RP) PSA outcomes following 6 versus 18 months of perioperative androgen receptor signaling inhibitors (ARSI) in men with localized high-risk prostate cancer: Results of Part 2 of a randomized phase 2 trial.
Authors: McKay Rana R. , Xie Wanling , Yang Xiaoyu , Acosta Andres , Rathkopf Dana E. , Laudone Vincent Paul , Bubley Glenn , Einstein David Johnson , Chang Peter , Wagner Andrew , Kane Christopher J. , Preston Mark A. , Kilbridge Kerry L. , Chang Steven Lee , Choudhury Atish Dipankar , Pomerantz Mark , Trinh Quoc-Dien , Kibel Adam S. , Taplin Mary-Ellen
Published: January 2024

326

Background: Patients with localized high-risk prostate cancer have an increased risk of relapse following RP. We previously reported on Part 1 of a phase 2 trial testing neoadjuvant apalutamide, abiraterone acetate, prednisone, plus leuprolide (AAPL) or abiraterone, prednisone, and leuprolide (APL) for 6 months followed by RP. We demonstrated favorable pathologic responses (tumor ≤5 mm) in 20.3% of patients (n=24/118). Herein, we report the results of Part 2 testing adjuvant AAPL. Methods: At Part 2, patients were randomized 1:1 to AAPL for 12 months (Arm 2A) or observation (Arm 2B), stratified by neoadjuvant therapy and pathologic T stage (200 ng/dL). Results: Overall, 69% (n=82/118) of patients enrolled to Part 1 were randomized to Part 2, of whom 58.5% (n=48) had ≥ ypT3 disease at RP. Patient preference was the main reason for non-randomization in Part 2. Of patients not randomized to Part 2, 32.3% (n=10) had a pathologic complete response or minimum residual disease (tumor ≤5 mm) at RP. In the intent-to-treat analysis, 3-year bPFS was 81% for Arm 2A and 72% for Arm 2B; the difference was not statistically significant (HR 0.81 90% CI 0.43-1.49). In a post-hoc per-protocol analysis, the 3-year bPFS was 83% for AAPL treated patients and 69% for patients on observation (HR 0.50 90% CI 0.26-0.97). Of patients randomized to Part 2, 81% of patients had testosterone recovery in the AAPL treated group compared to 95% in the observation group with median to recovery of 8.7 months compared to 4.0 months, respectively. Of the 37 patients receiving AAPL on Arm 2A, 28 (75.7%) experienced any grade treatment-related adverse event (TRAE) and 4 (10.8%) had grade 3-4 TRAE. The most common any grade TRAE were fatigue (27%) and hypertension (16%). Conclusions: Neoadjuvant ADT in localized high-risk prostate cancer resulted in favorable pathologic responses and 3-year bPFS in a subset of patients. As 30% of patients declined an additional 12 months of adjuvant treatment, Part B of the study was underpowered to detect a difference between treatment arms. Subsequent studies will evaluate clinical and molecular predictors of bPFS. Clinical trial information: NCT02903368 .
Deep learning (DL) algorithms to predict prostate cancer progression on low/intermediate-risk needle core biopsies.
Authors: Ding Chien-Kuang Cornelia , Vidotto Thiago , Erak Eric , De Paula Oliveira Lia , Bonthu Saikiran , Kondragunta Chaith , Joshi Uttara , Singhal Nitin , De Marzo Angelo M , Lotan Tamara L.
Published: January 2024

335

Background: Gleason Grade Group (GG) remains the standard of care to guide disease management in prostate cancer. Deep Learning (DL) algorithms assessing GG on whole slide images (WSI) have been largely validated by comparison to pathologist-determined GG. However, few studies have assessed DL grading of needle biopsies for predicting relevant clinical end-points. Methods: WSI of biopsies from two previously published cohorts (PMID 30279579, 27693448) were analyzed by a modified DL system for Gleason grading (PMID 35233002). In the Active Surveillance (AS) cohort (case-control design), all patients (n=137) had an initial biopsy with GG1 disease. Cases (63/137) had grade reclassification to GG2+ on repeat biopsies, or GG3+ or non-organ-confined disease by radical prostatectomy (RP), while the controls (74/137) continued on AS for >8 years without grade reclassification. For the Grade Group 2 (GG2) cohort, all patients (n=285) had GG2 disease on biopsy followed by RP, and progression was defined as biochemical recurrence (38/285). One representative H&E slide containing up to two biopsy cores from the diagnostic or confirmatory biopsy in both cohorts was graded by the DL system, and evaluated by 2-3 blinded uropathologists to provide consensus Gleason grading. Results: The agreement of GG between uropathologists and the modified DL system (κquad) was 0.32 for the AS cohort and 0.37 for the GG2 cohort. In the AS cohort, upgrading of the initial GG1 biopsy to GG2+ by the uropathologists occurred in 10% of cases compared to 7% of controls (p = 0.78). Upgrading by the DL system to GG2+ occurred in 33% of cases compared to 8% of controls (p=0.0005). In the GG2 cohort, biochemical recurrent after RP was not significantly associated with upgrading of the original biopsy to GG3+ by the uropathologists (HR= 0.55; 95% CI: 0.21-14.88; p=0.58) but significantly associated with upgrading by the DL system (HR=4.47; 95% CI: 1.32-15.09; p=0.01) in multivariable models including pre-operative PSA, clinical stage and fraction cores involved by tumor. Conclusions: In low or intermediate risk needle biopsies (GG1 and GG2), the agreement of grading between uropathologists and modified DL system is lower than that seen in analyses on a broader range of grade groups (PMID 35233002). Nevertheless, the DL system grading outperformed uropathologist consensus in predicting progression in patients with low/intermediate grade prostate cancer receiving active surveillance or radical prostatectomy.