bluuebunny/crossref_metadata_2025 huggingface dataset:
Distinction between clonal and paraclonal cutaneous involvements in VEXAS syndrome
Authors: Lacombe Valentin , Beucher Annaelle , Urbanski Geoffrey , Le Corre Yannick , Cottin Laurane , Croué Anne , Bouvier Anne
Published: February 2022

VEXAS (vacuoles, E1 enzyme, X-linked, auto-inflammatory, somatic) syndrome is an inflammatory disorder with hematological and systemic features. A recent study demonstrated that the dermal infiltrate in neutrophilic dermatosis from VEXAS patients is derived from the pathological UBA1-mutated myeloid clone. Neutrophilic dermatosis is, however, only one of the various skin involvements observed in VEXAS syndrome. We analyzed 10 formalin-fixed paraffin-embedded skin biopsies from genetically confirmed VEXAS syndrome. UBA1 mutation was found in the biopsies related to neutrophilic dermatitis but in none of the other histological patterns (leukocytoclastic vasculitis and septal panniculitis). This could lead to a distinction between clonal and paraclonal cutaneous involvements in VEXAS syndrome, which could in turn improve therapeutic outcomes.
Availability of informal social support and the impact on health services utilization among women in community corrections who engage in substance use and risky sexual behavior: New York City, 2009–2012
Authors: Hochstatter Karli R. , Slavin Melissa N. , Gilbert Louisa , Goddard-Eckrich Dawn , El-Bassel Nabila
Published: February 2022

Background

Women under community supervision in the U.S. experience high rates of substance use and HIV/STDs and face multiple barriers to healthcare services. Informal social support, provided by family, friends, and other peers, is important for reducing drug and sexual risk behaviors and improving utilization of healthcare services. The availability of informal social support and the impact on receipt of healthcare services among the growing and highly vulnerable population of sexually-active and drug- and justice-involved women has not been documented. Among this population, this study aims to: 1) describe characteristics of informal social support, including the prevalence of different types, size of networks, and frequency of receiving support; and 2) longitudinally examine the impact of informal social support on receipt of healthcare services, including drug or alcohol counseling/treatment, HIV or STD counseling/education, birth control counseling/education, reproductive healthcare, and individual counseling over a 12-month period.

Results

The sample included 306 women in community supervision programs in New York, New York, USA, with a recent history of substance use and risky sexual behavior. At baseline, 96.1% of women reported having at least one friend or family member with whom they could discuss personal or emotional problems, 92.5% had support for tangible aid or service, 83.0% had support for sexual risk reduction, and 80.0% had support for substance use risk reduction. Women with support for substance use risk reduction were more likely than women without this type of support to receive all health services analyzed in this study. Having support for sexual risk reduction was also positively associated will receipt of all services, except reproductive healthcare. Having support for personal or emotional problems was only associated with receiving drug or alcohol counseling or treatment, while having support for tangible aid or service did not impact receipt of any health services.

Conclusions

Engagement of sexually-active and drug- and justice-involved women in health services should address the availability and strengthening of informal social support, particularly ensuring individuals’ informal networks allow for discussions on the harms of risky sexual and drug use behaviors.

Trial registration

ClinicalTrials.govNCT01784809. Registered 6 February 2013 - Retrospectively registered.
Thinking about time: identifying prospective temporal illusions and their consequences
Authors: Tausen Brittany M.
Published: February 2022

Time is fundamentally abstract, making it difficult to conceptualize and vulnerable to mental distortions. Nine preregistered experiments identify temporal illusions that characterize prospective time judgments and corresponding consequences for decision making in a variety of domains. Using visual illusions as a grounding metaphor, studies 1–4 demonstrated that the temporal distance between two dates was perceived as closer together as those two dates were imagined further into the future (e.g., Vanishing Point); the length of a single day whether negative (e.g., a 12 h illness—Study 2a) or positive (e.g., 12 h with a good friend—Study 2b) was estimated to feel longer when embedded within a short versus long trip (e.g., the Delbouef Illusion); a 60 min activity was expected to go by more quickly when adjacent activities were 90 (vs. 30) min (e.g., Ebbinghaus Illusion); and a 9 + 1 day vacation was expected to be considerably lengthier than an 11–1 day vacation (e.g., Representational Momentum). Four additional studies explored moderating factors (Studies 5 and 6) and the impact of distortions on downstream non-time judgments including the forecasted emotional intensity of a negative event (Study 6), estimations of fair monetary compensation for lost time (Study 7), and willingness to make prosocial time commitments (Study 8). Implications for uncovering additional temporal illusions as well as practical applications for leveraging the relativity of prospective time to achieve desired cognitive and behavioral outcomes are discussed.
Isolation and characterization of compounds in ethanolic extract of Albizia coriaria (Welw ex. Oliver) leaves: a further evidence of its ethnomedicinal diversity
Authors: Omara Timothy , Kiprop Ambrose K. , Kosgei Viola J.
Published: February 2022

Background

Albizia coriariaWelw ex. Oliver (A. coriaria) is one of the treasured medicinal plants in Africa. In continuity of our study verifying the claim of using its leaves for managing bacterial diseases and oxidative stress-mediated complications in Ugandan traditional phytomedicine, we characterized its most active (ethanolic) extract using ultraviolet–visible (UV–Vis) spectroscopy, Fourier transform infrared (FTIR) spectroscopy, thin layer chromatography, column chromatography and gas chromatography–mass spectrometry.

Results

UV–Vis absorption peaks occurred between 338 and 664 nm, which indicated the presence of alkaloids, flavonoids and terpenoids. FTIR spectrum of the extract indicated the presence of O–H, C=O and aromatic–C=C which confirmed the presence of alcohols, carboxylic acids and aromatics in the extract. Four known bioactive triterpenoids: lupeol (1), lupenone (2), betulinic acid (3), betulin (4) along with an aromatic alcohol: benzyl alcohol (5) were tentatively identified in different fractions ofA. coriariaethanolic leaf extract. Compound4was identified for the first time in this species.

Conclusions

All the compounds identified in the fractions of theA. coriariaethanolic leaf extract have reported pharmacological activities, including antioxidant and antibacterial activities. This supports the traditional use ofA. coriarialeaves in the management of oxidative stress-mediated conditions and bacterial diseases in Uganda.
Takotsubo syndrome associated with cardioversion: a systematic review
Authors: Waheed Tayyab Ali , Nasir Usama , Aziz Ansar , Chaudhary Haseeb , Donato Anthony
Published: February 2022

Background

Direct current cardioversion is a well-established and safe procedure to restore normal sinus rhythm for atrial and ventricular arrhythmias. Takotsubo syndrome has been rarely described with cardioversion. We reviewed the literature for descriptions of Takotsubo syndrome associated with the stress of cardioversion, to better understand its risks.

Methods

We queried MEDLINE, EMBASE, Google Scholar and Cochrane for cases of Takotsubo syndrome secondary to synchronized cardioversion as defined by Mayo Clinic Diagnostic Criteria.

Results

We identified 11 cases of cardioversion-associated Takotsubo syndrome. Average age was 76 years (range: 61–87 years) and most (10 out of 11, 91%) were female. Diagnosis was made soon after cardioversion (median: 10 h, range: 0–48 h). Only 2 of 11 had ST elevations noted, while apical ballooning was noted in all cases. Pulmonary edema developed in 6 and cardiogenic shock developed in 5 patients. The median recovery time was 7 days (range: 3–11).

Conclusions

Cardioversion-associated TS has an overall favorable outcome with complete recovery in most cases. A higher risk of this complication may exist for elderly females undergoing synchronized cardioversion.
Impact of IL-28B gene polymorphism on chronic hepatitis-C patients progression with diabetes and non-diabetes
Authors: Ateya Rehab M. , Afifi Samir A. , Abd Al Monem Nagla , Al-Karamany Amira S. , Bessar Ahmed A. , Rageh Fatma , Ahmed Samar S. , Ghareeb Dalia
Published: February 2022

Background

Chronic hepatitis C (CHC) is a silent viral infection; however, elevated mortality and morbidity rates are noted in Egypt due to its adverse effects. The augmented incidence of diabetes in patients with viral C infection may be owing to glucose intolerance, high BMI, senility, and inherited factors.

Purpose of the study

Little information is available about the connection between interleukin-28B (IL-28B) genotype in disease progression among CHC patients with diabetes. Thus, we aimed to assess the association between IL-28B genotype (rs12979860) in CHC with type 2 diabetes mellitus (T2DM) versus those without diabetes in disease progression among Egyptian patients.

Results

CC genotype was significantly lower in diabetics than in non-diabetics (13.7% vs. 36.3%). While (CT/TT) were significantly higher in diabetics than in non-diabetics (CT 58.8% vs. 43.7%), (TT 27.5% vs. 20%) (p = 0.03) and likewise alleles (p = 0.04). Multivariate logistic regression analysis was significant with viral load p < 0.001, alanine aminotransferase (ALT) p < 0.001, genotype CC versus TT p = 0.04 & T2DM p = 0.03.

Conclusion

CC genotype might be used as a protective factor and TT genotype as a risk factor in disease progression among CHC patients with T2DM. Additionally, viral load, ALT & T2DM might interplay as predictors of disease severity. Detecting the genetic factors can be helpful in predicting and preventing the complications of diabetes associated with the hepatitis C virus (HCV).
The impact of asymptomatic ventricular arrhythmias on the outcome of heart failure patients with reduced ejection fraction
Authors: Sanhoury Mohamed , Mohamed Fatema , Sadaka Mohamed , Abdel-Hay Mohamed Ayman , Sobhy Mohamed , Elwany Mostafa
Published: February 2022

Background

Ventricular arrhythmias cause a significant proportion of sudden deaths. Several studies demonstrate a high prevalence of ventricular arrhythmias in patients with heart failure regardless of the etiology. The aim of this study was to determine the prevalence of silent ventricular arrhythmias in ambulatory heart failure patients with reduced left ventricular ejection fraction (HFrEF) and its correlation to the prognosis.

Results

Four hundred (400) ambulatory HFrEF patients on maximum tolerated doses of heart failure medications were included. Holter monitoring for 7 days was done in all patients searching for silent ventricular arrhythmias. The patients were followed-up for one year to detect the occurrence of major adverse cardiovascular events. We divided the study population into 2 groups based on an LVEF cutoff value of 30% (Group A < 30%, Group B ≥ 30%). Holter monitoring revealed ventricular arrhythmias in 304 patients. Patients with left ventricular ejection fraction (EF) < 30% (Group A) had more complex ventricular arrhythmias in the form of frequent Premature ventricular contractions (PVCs) of ≥ 5% and or non-sustained ventricular tachycardia (NSVT) runs. Furthermore, Among Group A, more major cardiovascular events were observed. Multivariate regression analysis showed that frequent PVCs and severely reduced LVEF were the strongest independent predictors of major cardiovascular events.

Conclusions

ventricular arrhythmias are common in HFrEF patients even in the compensated status. Both, left ventricular systolic function and the PVCs burden were found to be the strongest predictors of major adverse cardiovascular events.
Evaluation of a symptom-based score in combination with CA125 to predict ovarian malignancy in women with adnexal mass
Authors: Krishnamurthy Amruthamshu , Durairaj Jayalakshmi , Subbaiah Murali
Published: February 2022

Background

Adnexal masses are a common problem seen in women. The aim of this study was to determine the appropriate cut-off for symptom-based score to predict ovarian malignancy in women with adnexal mass and to evaluate it in combination with CA125.

Methods

This was a prospective study involving 341 women with adnexal mass who underwent surgery. A symptom-based scoring system was administered to the women, preoperatively, and CA125 levels were documented. Receiver operating characteristic curve (ROC) analysis was used to determine the appropriate cut-off for the symptom-based scoring. Results for this symptom-based scoring and CA125 were correlated with surgical pathological findings.

Results

Out of the 341 women with adnexal mass, 112 were diagnosed to have ovarian malignancy. The mean age of women was 43.6±13.8 years. Using ROC analysis, symptom score ≥9 was determined to be the appropriate cut-off. The area under curve (AUC) at this cut-off score was found to be 0.87 (95% CI 0.83–0.91). The sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) at this cut-off was found to be 84.8%, 88.6%,78.5%, and 92.3%, respectively. Combining CA125 and symptom score resulted in higher sensitivity (96.4%) and NPV (97.4%) with specificity and PPV of 65.5% and 57.8%, respectively.

Conclusion

Symptom score in combination with CA125 has good ability to predict ovarian malignancy in women with adnexal masses.
The “case” for case studies: why we need high-quality examples of global implementation research
Authors: Beecroft Blythe , Sturke Rachel , Neta Gila , Ramaswamy Rohit
Published: February 2022

Rigorous and systematic documented examples of implementation research in global contexts can be a valuable resource and help build research capacity. In the context of low- and middle-income countries (LMICs), there is a need for practical examples of how to conduct implementation studies. To address this gap, Fogarty’s Center for Global Health Studies in collaboration with the Cincinnati Children's Hospital Medical Center and the National Cancer Institute is commissioning a collection of implementation science case studies in LMICs that describe key components of conducting implementation research, including how to select, adapt, and apply implementation science models, theories, and frameworks to these settings; develop and test implementation strategies; and evaluate implementation processes and outcomes. The case studies describe implementation research in various disease areas in LMICs around the world. This commentary highlights the value of case study methods commonly used in law and business schools as a source of “thick” (i.e., context-rich) description and a teaching tool for global implementation researchers. It addresses the independent merit of case studies as an evaluation approach for disseminating high-quality research in a format that is useful to a broad range of stakeholders. This commentary finally describes an approach for developing high-quality case studies of global implementation research, in order to be of value to a broad audience of researchers and practitioners.
Coupling relationship between current in-situ stress and natural fractures of continental tight sandstone oil reservoirs
Authors: Cui Xinying , Radwan Ahmed E.
Published: February 2022

We have integrated rock mechanics and acoustic experiments, full-wave array acoustic testing, formation microscanner image logging, and hydraulic-fracturing data to evaluate the coupling relationship between current in-situ stress and natural fractures. We used the data of the Yanchang Formation in the DL block of the western Ordos Basin, China, as an example. Our results find that the Yanchang Formation mainly develops high-angle fractures and vertical fractures. Furthermore, the in-situ stress state of the target sandstone strata satisfies [Formula: see text]. Nearly vertical and high-angle fractures are formed in the environment when [Formula: see text] is the maximum principal stress. Therefore, the current in-situ stress state of the target layer matches the induced fractures (longitudinal tensile-induced fractures) and natural fractures. As the buried depth increases, the difference between the horizontal maximum and minimum stresses ([Formula: see text]) has a tendency to first decrease and then increase, and its conversion depth is approximately 2000 m. Natural fractures are not developed in the distributary bay (the lowest horizontal stress area) and the thick sand area in the middle of the main river channel (the largest horizontal stress area). Natural fractures are mainly developed on the two wings of the main channel, and their horizontal stress is approximately 2–4 MPa lower than the central part of the main channel. We determined a correlation between fractures and sedimentary facies, and we have an important reference value for improving the drilling success rate of tight oil reservoirs. Furthermore, our study provides insights into the prediction of fractures and sweet spots for further exploration and hydraulic fracturing activities in the studied area and elsewhere in continental tight sandstone reservoirs.
Comprehensive genomic profiling of penile squamous cell carcinoma and impact of HPV status on immune-checkpoint inhibition-related biomarkers.
Authors: Nazha Bassel , Wu Sharon , Brown Jacqueline T , Magee Daniel , Carthon Bradley Curtis , Kucuk Omer , Korn W. Michael , Barata Pedro C. , Heath Elisabeth I. , Ryan Charles J. , McKay Rana R. , Master Viraj A. , Bilen Mehmet Asim
Published: February 2022

4

Background: Penile squamous cell carcinoma (SCC) is a rare and aggressive malignancy with few treatments in the advanced setting and little success of immune-checkpoint inhibitions (ICI). Around half of penile SCC cases are linked to HPV infection. We aimed to report the landscape of somatic alterations and ICI-related biomarkers in penile SCC in the Caris Life Sciences dataset and to establish signatures for HPV-dependent and HPV-independent oncogenesis. Methods: Penile SCC tumors were analyzed using next-generation sequencing of DNA (TruSeq, 45 genes; NextSeq, 592 genes and NovaSeq, whole exome sequencing (WES)) and RNA (NovaSeq). PD-L1 expression was tested by IHC using SP142. Microsatellite instability (MSI) was tested by fragment analysis, IHC and NGS. Tumor mutational burden (TMB) was measured by counting all somatic mutations found per tumor (TMB-high: >10 mutations per MB). HPV16/18 status was determined using WES when available. Significance was determined using chi-square and Wilcoxon rank sum test and adjusted for multiple comparisons (q-value <0.05). Results: Among the entire cohort (N=108), the median age was 66 years and 79.6% of tumors were primary and 20.4% of tumors were metastatic. In the overall cohort, the most frequently detected mutations were TP53 (46%), CKDN2A (26%), PIK3CA (25%), TERT promoter (22%), KMT2C (16%) and NOTCH1 (14%), consistent with previous reports. Overall, 51% of tumors were PD-L1+ (SP142, >1%), 10.7% had high TMB, and 1.1% had dMMR/MSI-H. Of the 108 tumors, 29 had HPV status tested by WES (HPV16/18+, n=13 and HPV16/18-, n=16). KMT2C mutations (33% vs 0%) and FGF3 amplifications (30.8% vs 0%) were specific to HPV16/18+ tumors, while CDKN2A mutations (37.5% vs 0%) were exclusive to HPV16/18- tumors. HPV16/18+ tumors also had a trend towards decreased TP53 (7.7% vs 63%) and TERT promoter (25% vs 77%) alterations (Table). TMB-high were exclusively found in the HPV16/18+ group (30.8% vs 0%), while PD-L1 and dMMR/MSI-H status were comparable between the two groups. Conclusions: To our knowledge, our comprehensive NGS study of penile SCC somatic alterations is the largest to date. HPV16/18+ vs HPV16/18- penile SCC were molecularly distinct tumors, consistent with previous reports. Our finding that TMB-high was exclusive to patients with HPV16/18+ tumors requires confirmation in larger datasets and could be used for better patient stratification in ICI clinical trials.[Table: see text]
Impact of COVID-19 on the incidence of prostate cancer among White and Black Veterans.
Authors: Lee Kyung Min , Guram Kripa , Alba Patrick , Anglin-Foote Tori , Robison Brian , Rose Brent S , Lynch Julie Ann
Published: February 2022

29

Background: Early-stage prostate cancer (PCa) is typically detected on prostate-specific antigen (PSA) screening and subsequent prostate biopsy, healthcare interventions that are considered routine elective procedures. The COVID-19 pandemic disrupted routine healthcare screenings and interventions. We sought to determine whether delayed screening and diagnostic workup of PCa was associated with increased rates of incident PCa, high-grade Gleason, and metastatic disease at diagnosis. Methods: We used the Corporate Data Warehouse of the Veterans Health Administration to collect PSA, prostate biopsy, PCa diagnosis, Gleason score, and metastasis information of White and Black Veterans aged 40 years or older newly diagnosed with PCa from January 2019 through June 2021. For each month, we calculated rates of PSA, prostate biopsy, and incident PCa per 100,000 men and plotted monthly rates by race. We performed descriptive analyses to compare age at first PSA, age at diagnosis, baseline PSA, Gleason scores, and metastasis pre- and post-January 2020, the month in which the U.S. declared COVID-19 a public health emergency. Results: The decrease in the rate of PSA screening immediately after January 2020 was similar in both White and Black Veterans (7% vs. 6%). However, the magnitude of reduction in the rate of prostate biopsy and the rate diagnosis of incident PCa were five times larger among Black Veterans compared to White Veterans (11% vs. 2% for both biopsy and diagnosis rates). Among the 17,771 White and 9,610 Black Veterans with incident PCa, the rate of Gleason of 4+3 or greater and the rate of metastatic disease at diagnosis increased three months after the pandemic in both race groups with comparable magnitude (2-3% increase in high-grade Gleason, 1% increase in metastatic disease). Conclusions: Utilization patterns indicated that while the decrease in PSA screening after the pandemic was similar in White and Black Veterans, reductions in prostate biopsy and diagnosis of incident PCa were five times greater in Blacks than Whites. Further research including risk-adjusted modeling is needed to determine whether Black Veterans were disproportionately affected by the pandemic-related disruptions in PSA screening and diagnostic workup of prostate cancer.[Table: see text]
Real-world health-related quality of life and caregiver need in patients with metastatic hormone-sensitive and metastatic castration-resistant prostate cancer.
Authors: Boye Mark , Ribbands Amanda , Leith Andrea , Clayton Emily , Butcher Jake , Rybowski Sarah
Published: February 2022

54

Background: Prostate cancer (PC) is one of the most common cancers in men. When making treatment decisions, patient health-related quality of life (HRQoL) and caregiver need are important considerations, and as such it is imperative to understand the impact that PC has on HRQoL. We aimed to assess the impact of metastatic hormone-sensitive PC (mHSPC) and castration-resistant PC (mCRPC) on HRQoL and associated caregiver need. Methods: Real-world data were drawn from the PC Disease Specific Programme, a point-in-time survey conducted in the United States of America and Europe (France, Germany, Italy, Spain and the United Kingdom) between Jan-Aug 2020. Physicians completed patient record forms for their next 8 consecutively consulting adult metastatic PC patients (4 mHSPC/4 mCRPC). Eligible patients were invited to complete a voluntary patient self-reported form on caregiver need and HRQoL including EuroQol 5-dimension 5-level (EQ-5D-5L), EuroQol Visual Analogue Scale (EQ-VAS), Functional Assessment of Cancer Therapy – General/Prostate (FACT-G/P) and Brief Pain Inventory (BPI) questionnaires. Higher scores indicate better HRQoL and more pain. Data were analysed descriptively. Results: 376 mHSPC and 331 mCRPC patients completed patient self-reported forms. Demographics and clinical characteristics for mHSPC/mCRPC patients were: mean age 71.1/71.5 years, 77%/69% of patients had an ECOG performance status of 0-1, 82%/83% of patients were retired and 42%/44% of patients had a caregiver. At data collection, mean HRQoL scores for mHSPC/mCRPC patients were: 66.4/63.4 (EQ-VAS), 0.76/0.72 (EQ-5D-5L), 66.2/62.9 (FACT-G) and 94.6/90.2 (FACT-P). Patients with mHSPC had FACT-P social, emotional, functional and physical well-being subscale scores of 18.2, 14.7, 13.6 and 19.7, respectively. These scores were 17.7, 14.0, 12.7 and 18.5 in mCRPC patients, respectively. Mean “worst pain” scores were mild (3.6/3.9 on BPI for mHSPC/mCRPC patients). In terms of both non-professional and professional caregivers, mHSPC/mCRPC patients reported a mean of 31.6/28.9 care hours/week. Most caregivers were partners/spouses (in 89% of mHSPC and 82% of mCRPC patients) providing a mean of 29.0 and 27.7 care hours/week, respectively. Conclusions: We showed that HRQoL and well-being are impacted in both mHSPC and mCRPC patients, and that there is a considerable time burden on caregivers. Patients with mCRPC reported the lowest HRQoL scores and highest pain scores, suggesting that patients who are sicker may have greater disease burden. Our findings suggest an unmet need for HRQoL in patients with mHSPC and mCRPC, and also a need for greater caregiver support in these patients.
Treatment outcomes for metastatic castration-resistant prostate cancer (mCRPC) following progression on upfront androgen deprivation therapy (ADT) with androgen receptor pathway inhibitors (ARPI) for metastatic castration-sensitive prostate cancer (mCSPC).
Authors: Khalaf Daniel Joseph , Chen Liheng , Sunderland Katherine , Vergidis Joanna , Noonan Krista , Finch Daygen L. , Zulfiqar Muhammad , Chi Kim N.
Published: February 2022

60

Background: Combined ADT and ARPI is associated with improved overall survival (OS) compared with ADT alone in patients with mCSPC. The activity of subsequent therapies for mCRPC is not well characterized. Methods: We conducted a retrospective analysis of patients enrolled on a biobank at 6 cancer centres in British Columbia, Canada. Patients who received abiraterone or apalutamide for mCSPC were included. Data including baseline clinical prognostic factors and clinical outcomes (per Prostate Cancer Working Group III) were collected from patient records. Survival was analyzed by Kaplan-Meier method and Log Rank test and prognostic variables were determined using Cox regression. Results: 168 patients were identified of which 126 (75%) received abiraterone, 38 (23%) received apalutamide, and 4 (2%) received one ARPI and switched to the other for toxicity. Median age was 69 years and Gleason score ≥ 8 in 61%. Site of metastasis (mets) at mCSPC was lymph node (n=91), bone (n=141), and liver (n=6). As of August 28 2021, a total of 46 patients progressed to mCRPC, of which 38 received subsequent systemic therapy. First-line mCRPC treatments were docetaxel (n=12), Radium-223 (10), enzalutamide (6), platinum chemotherapy (3), and others (7) including immune checkpoint inhibitors (1) and Lutetium177-PSMA-617 (1) and other investigational agents (5). Outcomes are shown in the table. On univariate Cox analysis, clinical factors at time of mCRPC associated with worse OS were: LDH above upper limit of normal (HR 5.0, 95% CI 1.7-14.5), hemoglobin below lower limit of normal (5.2, 1.1-23.8), presence of ≥ 20 bone mets (3.7, 1.4-9.8), and increasing PSA (1.002, 1.001-1.003). Conclusions: PSA decline rates and survival are modest for patients who have progressed following upfront abiraterone or apalutamide plus ADT for mCSPC. Further follow-up is required to accurately determine outcomes with current mCRPC standard therapies following up-front ADT+ ARPI. Recently approved treatment options such as Lutetium177-PSMA-617 and PARP inhibitors for DNA damage repair deficient tumors may help to improve outcomes for these patients.[Table: see text]
Baseline parameters of patients with prostate cancer (PCa) initiating a triptorelin treatment for at least 12 months in real life, TALISMAN study interim analysis.
Authors: Thiery-Vuillemin Antoine , Rigaud Jerome , Crehange Gilles , Pello Leprince Ringuet Nathalie , Grandoulier Anne-Sophie , Lebret Thierry
Published: February 2022

61

Background: Little is known on modalities of use of androgen deprivation therapy (ADT) in real life. They may depend on tumor aggressiveness, patient frailty and physician habits. Our purpose was to describe reasons of choice of planned total duration of triptorelin treatment, mainly according to circumstances of prescription. Methods: Initiated in November 2020, a prospective, multicenter, non-interventional study is conducted in France (TALISMAN). Urologists, radiation oncologists and medical oncologists recruited patients with histologically confirmed PCa, eligible for triptorelin therapy within its label, with a planned total duration of at least 12 months. Decision of triptorelin treatment was made before inclusion, in routine practice. 786 patients were planned to be enrolled, with a 12-month follow-up. Primary objective is to describe the proportion of patients treated continuously with triptorelin during the 12 months following treatment initiation. Interim analysis was planned when 50% of patients are enrolled, its objective was description of subgroups according to circumstance of prescription, planned total duration of triptorelin treatment, formulation/route of triptorelin prescribed, specialty of investigators. No statistical test was performed. Results: 509 patients were included in the interim analysis. Patients were mostly enrolled by urologists (56.8%) and radiation oncologists (40.1%). Mean age ±SD was 73.9±8.0 years; 70.9% had at least one comorbidity; 72.1% had a Gleason score ≥ 4+3; 65.2% had at least one concomitant PCa treatment. Main baseline parameters are presented in Table. Subgroups description showed that patients with high risk localized and patients with locally advanced PCa were most often offered a [24-36] month planned treatment duration (respectively 53.6% and 40.6%), in accordance with the guidelines. Reasons of choice of the planned total duration mainly refer to Gleason score (27.6%) and PSA level (19.4%). Reasons of choice of formulation/route of triptorelin prescribed mainly refer to physician preferred formulation/route (47.7%) and planned total duration of ADT (29.9%). Conclusions: The ongoing TALISMAN study is collecting data on patients, PCa aggressiveness, supportive care, which may impact total duration of triptorelin treatment. Statistical analyses at completion of study will give additional results. Clinical trial information: NCT04593420. [Table: see text]
Treatment trends among men with metastatic castration sensitive prostate cancer (mCSPC): Results from the US component of an international study.
Authors: Barata Pedro C. , Leith Andrea , Ribbands Amanda , Montgomery Rachel , Last Matthew , Arondekar Bhakti , Niyazov Alexander , Ivanova Jasmina
Published: February 2022

66

Background: Novel hormonal therapies (NHTs) and taxane-based chemotherapy (CT) were initially approved for the treatment of metastatic castration resistant prostate cancer (mCRPC) and are now approved for use in mCSPC. Little is known about the recent uptake of these treatments in mCSPC. This study evaluated mCSPC treatment trends from 2016 to 2020 in the US. Methods: Participating physicians collected information from medical charts for the next consecutive 8 men with advanced prostate cancer (4 men with mCSPC, and 4 men with mCRPC) during January-August 2020. A subset of men with current mCRPC had historical mCSPC treatment information available. Treatments were categorized into 4 mutually exclusive categories: (1) androgen deprivation therapy (ADT) ± first-generation anti-androgen (1st gen AA); treatment intensification with (2) NHT, (3) taxane CT ± NHT, and (4) other treatments (e.g., radium-223, sipuleucel-T, non-taxane CT). To account for the availability of new mCSPC treatments, treatment patterns across all lines of mCSPC therapy were described for men initiating treatment in 2016-2018 and 2019-2020. Results: 239 men with mCSPC were included (146 with mCSPC at data collection; 93 with mCRPC at data collection and who had historical information on mCSPC treatments). Mean age was 69 years; 69% had bone metastases and 30% had visceral metastases. Most patients were managed by oncologists (75%), while 48% were treated at academic/cancer centers. From 2016-2018 to 2019-2020, mCSPC treatment intensification with NHT increased while treatment intensification with taxane CT or other therapies declined. (Table) Conclusions: In this real-world study of adult men with mCSPC, increased use of NHT was observed over time indicating that more men will have been exposed to NHT when they progress to mCRPC. This suggests an unmet need for novel therapies in mCRPC. Funding: Pfizer. [Table: see text]
Association between patient-reported outcomes (PROs) and changes in prostate-specific antigen (PSA) in patients (pts) with advanced prostate cancer treated with apalutamide (APA) in the SPARTAN and TITAN studies.
Authors: Small Eric Jay , Chi Kim N. , Chowdhury Simon , Bevans Katherine B. , Bhaumik Amitabha , Saad Fred , Chung Byung , Karsh Lawrence Ivan , Oudard Stephane , De Porre Peter , Brookman-May Sabine D. , McCarthy Sharon Anne , Mundle Suneel , Uemura Hirotsugu , Smith Matthew Raymond , Agarwal Neeraj ,   On behalf of the SPARTAN and TITAN investigators
Published: February 2022

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Background: In phase 3 placebo (PBO)-controlled studies, addition of APA to androgen deprivation therapy (ADT) improved overall survival, resulted in rapid and deep PSA declines, and reduced risk of disease progression while preserving health-related quality of life (HRQoL) in nonmetastatic castration-resistant prostate cancer (nmCRPC; SPARTAN) and metastatic castration-sensitive prostate cancer (mCSPC; TITAN). This post hoc analysis evaluated the association of a deep PSA decline with PROs in these studies. Methods: Pts on ADT were randomized to APA (240 mg QD) or PBO: SPARTAN 2:1 (N = 1,207; APA n = 806), TITAN 1:1 (N = 1,052; APA n = 525). Each cycle was 28 d. PROs were assessed using Functional Assessment of Cancer Therapy-Prostate (FACT-P), Brief Pain Inventory-Short Form (BPI-SF; TITAN only), and Brief Fatigue Inventory (BFI; TITAN only) at baseline, specific cycles during study treatment, and post progression up to 1 yr. A landmark analysis at Month 3 evaluated association between deep PSA decline (≤ 0.2 ng/mL) and time to subsequent deterioration in PROs (defined as decrease ≥ 10 points FACT-P total, ≥ 3 points Physical Wellbeing, ≥ 30% baseline for BPI-SF worst pain, or ≥ 2 points for BFI worst fatigue). At time of the landmark analysis, only pts continuing treatment were included; all deep PSA responses after, and all PRO deterioration events before, were ignored. Time-to-event end points were analyzed by Kaplan-Meier method and Cox proportional hazards model. Results: Median treatment durations were 32.9 mo (SPARTAN) and 39.3 mo (TITAN). Per assessment, > 90% (SPARTAN, cycles 1-81) and > 50% (TITAN, cycles 1-33) of eligible pts completed FACT-P; BPI-SF and BFI, both > 62% (TITAN, cycles 1-33). Pts in either study who achieved PSA ≤ 0.2 ng/mL at Month 3 had a lower risk of deterioration in FACT-P total or Physical Wellbeing (Table). Pts in TITAN with PSA ≤ 0.2 ng/mL at Month 3 had a lower risk of BPI-SF worst pain intensity or BFI worst fatigue intensity progression (Table). Conclusions: Deep and rapid PSA responses with APA were associated with prolonged time to deterioration in HRQoL, FACT-P Physical Wellbeing, BPI-SF worst pain intensity, and BFI worst fatigue intensity in pts with advanced PC. Clinical trial information: NCT02489318 (TITAN); NCT01946204 (SPARTAN). [Table: see text]
Daily symptom monitoring commonly leads to treatment modification in older adults receiving treatment for metastatic prostate cancer (mPC).
Authors: Breunis Henriette , Sudharshan Abirami , Emmenegger Urban , Hansen Aaron Richard , Soto Perez De Celis Enrique , Finelli Antonio , Tomlinson George , Warde Padraig , Krzyzanowska Monika K. , Matthew Andrew , Clarke Hance , Santa Mina Daniel , Puts Martine , Alibhai Shabbir M.H.
Published: February 2022

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Background: Treatment options for older adults with mPC expanded significantly in recent years but commonly include chemotherapy with Docetaxel (Chemo), androgen receptor-axis-targeted therapies (ARAT), and Radium-223 (Ra-223). Symptom burden associated with Chemo, ARAT, and Ra-223 is frequently observed and often leads to treatment modification, especially in older men. The objective of this study is to explore how often, and which moderate to severe symptoms during treatment for mPC and triggered follow-up, lead to treatment delay and/or dose reduction. Methods: Men aged 65+ with mPC starting standard dose (n=24) or reduced dose (n=1) Chemo, standard dose (n=41) or reduced dose (n=1) ARATs, or Ra223 (n=12) from two tertiary cancer centres in Toronto, Canada, were enrolled in a prospective cohort study. Participants self-reported symptoms daily using the Edmonton Symptom Assessment Scale (ESAS) for 3-4 weeks either through a web-based interface or phone calls. ESAS scores of >4 were followed by ‘triggered’ detailed questionnaires. The oncology care team was informed of reportable events based on scores of triggered questionnaires and patients were advised to call their care team. Clinical and treatment data were abstracted from electronic patient records and descriptive analysis was used. Results: 52/79 participants (66%) reported 345 moderate to severe symptoms that merited triggered questionnaires (table) with an adherence of 83%. Tiredness (n=74), appetite (n=49), insomnia (n=49), and pain (n=48) were the most frequently reported symptoms. 28 patients reported high scores on triggered questionnaires that led to informing the oncology care team and 79% of these patients were contacted by the care team, or an appointment with the Most Responsible Physician was scheduled. Moderate to severe symptom reporting resulted in treatment modification for 9 patients, Chemo (n=5), ARAT (n=3), and Ra-223 (n=1). Conclusions: Daily monitoring identified clinically relevant symptoms and actionable concerns. Informing care teams of reportable adverse events resulted in contacting patients and ultimately in treatment modification in a considerable number of patients. [Table: see text]
The effect of prior docetaxel (DOC) treatment on efficacy and safety of apalutamide (APA) plus androgen deprivation therapy (ADT) in patients (pts) with metastatic castration-sensitive prostate cancer (mCSPC) from TITAN.
Authors: Chi Kim N. , Merseburger Axel S. , Ozguroglu Mustafa , Chowdhury Simon , Bjartell Anders , Chung Byung , Pereira de Santana Gomes Andrea Juliana , Given Robert , Juárez Álvaro , Uemura Hirotsugu , Ye Dingwei , Karsh Lawrence Ivan , Gartrell Benjamin Adam , Brookman-May Sabine D. , Mundle Suneel , McCarthy Sharon Anne , Lefresne Florence , Rooney Oliver Brendan , Bhaumik Amitabha , Agarwal Neeraj
Published: February 2022

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Background: Addition of androgen receptor signaling inhibitors to ADT + DOC has been shown to improve clinical outcomes in pts with mCSPC. TITAN, a placebo-controlled phase 3 study, showed that APA + ADT improved overall survival (OS) and other clinical outcomes in mCSPC (Chi, J Clin Oncol 2021). This post hoc analysis of TITAN evaluated outcomes in pts who had received DOC prior to treatment with APA + ADT versus those who did not. Methods: In TITAN, 1052 pts were randomized 1:1 to APA (240 mg QD) or placebo added to ongoing ADT. We assessed radiographic progression-free survival (rPFS), OS, and time to prostate-specific antigen (PSA) progression in pts receiving DOC and ADT prior to adding APA vs those receiving only ADT plus APA. Outcomes by prior DOC were also assessed in pts with high- or low-volume disease at randomization (baseline [BL]) per adapted CHAARTED criteria, or those with matched BL characteristics. A Cox proportional hazards model was used to derive hazard ratios (HRs) and p values. rPFS was assessed using the first interim analysis cutoff (23 mo median follow-up); OS and time to PSA progression were assessed using the final analysis cutoff (44 mo median follow-up). Results: A total of 58/525 (11%) pts from the APA + ADT group had received DOC prior to randomization: 76% (n = 44) had high-volume disease, 62% (n = 36) had bone-only metastases, 16% (n = 9) had visceral metastases, and 59% (n = 34) had > 10 bone lesions. In the overall APA-treated population and in the subset of pts with high-volume disease, OS, rPFS, and time to PSA progression were similar in those who received prior DOC and those who did not (Table). Pts with low-volume disease also had similar results, although the number of pts was small. Clinical outcomes in pts with matched BL characteristics (including PSA and time from initial diagnosis to randomization, among others) were similar regardless of prior use of DOC (Table). The safety profile of APA was not substantially different between pts with or without prior DOC. Limitations of this analysis include lack of data on tumor volume and other disease characteristics at the initiation of prior DOC treatment; interpretation was based on small number of pts with prior DOC (only 11% of TITAN pts), most notably in the rPFS analysis. Conclusions: Prior use of DOC in pts with mCSPC did not further improve clinical benefits of APA + ADT in TITAN. Clinical trial information: NCT02489318. [Table: see text]
Impact of concomitant cardiovascular therapies on efficacy and safety of relugolix verus leuprolide in men with advanced prostate cancer: Subgroup analysis from the phase 3 HERO study.
Authors: Shore Neal D. , George Daniel J. , Mehlhaff Bryan Allyn , Cookson Michael , Saltzstein Daniel , Tutrone Ronald F. , Brown Bruce , Lu Sophia , Lee Jina , Hanson Sarah , Saad Fred
Published: February 2022

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Background: Cardiovascular (CV) events are the leading cause of death in prostate cancer. Men with prostate cancer are likely to have CV risk factors and CV-related concomitant medications. In the phase 3 HERO study, a 54% lower incidence of major adverse cardiac events was reported in men treated with the oral GnRH receptor antagonist relugolix vs leuprolide. Herein, we characterize the impact of concomitant CV therapies on efficacy and safety in the HERO study. Methods: In HERO, 930 men with advanced prostate cancer were randomized 2:1 and treated with relugolix (120 mg orally once daily [after single 360 mg loading dose] or leuprolide (injections every 3 months) for 48 weeks. Subgroups analyzed included men who received antihypertensives, antithrombotics, or lipid-modifying therapies, as well as the most common drug classes (>10%) and single most common agent within each class. Assessments included sustained testosterone suppression to castrate levels (<50 ng/dL) through 48 weeks and safety parameters (adverse events). Results: Antihypertensives, antithrombotics, and lipid modifying agents were utilized by 52.7%, 39.1%, and 39.6% of men in the HERO trial, respectively (table). In the main subgroups, point estimates for sustained castration rates were consistent with the overall estimates of relugolix and leuprolide observed in the overall population (table). Sustained castration rates were also consistent for men taking the most common drug classes (table) and individual agents in each class (losartan [n=103]: relugolix, 95.4% vs. leuprolide, 80.6%; amlodipine [n=229]: 97.2% vs. 85.5%; metoprolol [n=88]: 95.7% vs. 86.9%; acetylsalicylic acid [n=259]: 97.0% vs. 92.1%; clopidogrel [n=43]: 96.4% vs. 86.7%; simvastatin [n=78]: 98.0% vs. 87.3%). Incidence and types of adverse events were similar among men who received antihypertensives, antithrombotics, and lipid modifying agents during the trial. Conclusions: In the HERO trial, relugolix suppressed testosterone and was generally well tolerated when given with concomitant CV agents, with results consistent with those of the overall population. Clinical trial information: NCT03085095. [Table: see text]
The immunocytokine M9241 in the treatment of prostate cancer (PCa): Clinical and immune data from a phase 1 study.
Authors: Meininger Luke , Madan Ravi Amrit , Toney Nicole , Donahue Renee Nicole , Gatti-Mays Margaret Elena , Strauss Julius , Karzai Fatima , Bilusic Marijo , Marte Jennifer L. , Cordes Lisa M. , Redman Jason , Floudas Charalampos S. , Pastor Danielle M. , Figg William Douglas , Dahut William L. , Schlom Jeffrey , Gulley James L.
Published: February 2022

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Background: Interleukin-12 (IL-12) is a proinflammatory cytokine that plays a critical role in regulating the transition from innate to adaptive immunity but has toxicity with systemic administration. M9241 is an immunocytokine composed of 2 IL-12 heterodimers, each fused to one of the H-chains of the NHS76 antibody, which has affinity for both single and double stranded DNA. Thus, M9241 targets delivery to regions of tumor necrosis where DNA has become exposed. NCT01417546, a phase I trial of M9241 at escalating doses, established safety and dosing (Strauss J et al, CCR 2019). This was the first use of M9241 in human subjects with solid tumors including PCa. Methods: Nine patients (pts) with PCa enrolled in the phase 1 study, not all of which were presented previously. M9241 was given subcutaneously every 4 weeks (0.1-21.8mcg/kg) or every 2 weeks (12-16.8mcg/kg). PSA declines and immune responses were evaluated including systemic cytokine levels and 30 markers on 158 circulating immune cell subsets. Results: Nine PCa pts were treated with NHS-IL12 and 8 were evaluable for response, including 6 pts with biochemical recurrence and 2 with metastatic castration resistant prostate cancer (one patient discontinued the study treatment after 1 dose due to grade 3 elevation in ALT). There were no adverse events (AEs) of grade >4. Additional grade 3 toxicities included one each of: leukopenia, neutropenia and lymphopenia. The most common AEs of any grade were lymphopenia (77.8%), fatigue (55.6%), and ALT elevation (55.6%). 5 of 8 (62.5%) had PSA declines ranging from 8-42%. After treatment with M9241, evaluable pts had increases in systemic IL-10, TNF and INFg. Additional immune changes included increases in activated subpopulation of natural killer (NK) cells, consistent with the phase 1 experience. Conclusions: M9241 was found to be safe and well tolerated in PCa pts. PSA declines occurred in 5 of 8 evaluable pts. As with the phase 1 study, increases in NK subpopulations were seen in the small number of evaluable pts. These preliminary findings of a necrosis-targeting immunocytokine will be evaluated further in combination studies with cytotoxic therapy. M9241 is currently being evaluated in combination with docetaxel in metastatic prostate cancer (NCT04633252). Clinical trial information: NCT01417546.