bluuebunny/crossref_metadata_2025 huggingface dataset:
Improving cardiovascular health in patients with an abdominal aortic aneurysm: development of the cardiovascular risk reduction in patients with aneurysms (CRISP) behaviour change intervention
Authors: Withers Tom M. , Greaves Colin J. , Bown Matt J. , Saratzis Athanasios
Published: January 2024

Background

Abdominal aortic aneurysm (AAA) is an important cardiovascular health problem. Ultrasound screening is proven to reduce AAA mortality and programmes have been implemented in some healthcare systems. Those who are identified as having a small AAA in screening enter into a surveillance programme to monitor AAA size. Individuals in AAA surveillance are at elevated risk of cardiovascular events, which is not currently addressed sufficiently. We aimed to develop a simple intervention to reduce cardiovascular risk, which could be embedded in AAA surveillance pathways.

Methods

Intervention mapping methods were used to co-develop the intervention with individuals with AAA, families/carers, and healthcare staff. We identified “targets for change” by synthesising research evidence and international guidelines and consulting with patients, caregivers and health service providers. We conducted a series of workshops to identify barriers to and facilitators of change and used taxonomies of behaviour change theories and techniques to match intervention strategies to each target. Further stakeholder involvement work helped refine the intervention.

Results

The developed intervention focusses on assessment and individually tailored discussion of risk factors, exchanging information, building motivation and action planning, followed by review of progress and problem-solving. Workbooks covering physical activity, diet, stress management, alcohol, smoking, blood pressure and mental health are provided to support behaviour change. The intervention is facilitated by trained healthcare professionals during the patient’s AAA screening appointment for the duration that they are in surveillance.

Discussion

The developed intervention will now be tested to assess whether it can be integrated with the current AAA screening programme. The developed intervention is a novel approach to reducing cardiovascular disease in the AAA population, it is also the first intervention which tries to do this in this population.

Trial registration

International Clinical Trial Registration: ISRCTN93993995.
A hybrid econometrics and machine learning based modeling of realized volatility of natural gas
Authors: Kristjanpoller Werner
Published: January 2024

Determining which variables affect price realized volatility has always been challenging. This paper proposes to explain how financial assets influence realized volatility by developing an optimal day-to-day forecast. The methodological proposal is based on using the best econometric and machine learning models to forecast realized volatility. In particular, the best forecasting from heterogeneous autoregressive and long short-term memory models are used to determine the influence of the Standard and Poor’s 500 index, euro–US dollar exchange rate, price of gold, and price of Brent crude oil on the realized volatility of natural gas. These financial assets influenced the realized volatility of natural gas in 87.4% of the days analyzed; the euro–US dollar exchange rate was the primary financial asset and explained 40.1% of the influence. The results of the proposed daily analysis differed from those of the methodology used to study the entire period. The traditional model, which studies the entire period, cannot determine temporal effects, whereas the proposed methodology can. The proposed methodology allows us to distinguish the effects for each day, week, or month rather than averages for entire periods, with the flexibility to analyze different frequencies and periods. This methodological capability is key to analyzing influences and making decisions about realized volatility.
Performance-based assessment in virtual versus non-virtual classes: impacts on academic resilience, motivation, teacher support, and personal best goals
Authors: Aladini Alaa , Bayat Sania , Abdellatif Mohamed Sayed
Published: January 2024

This study investigated the Performance-Based Assessment (PBA) impact on academic resilience (AR), motivation, teacher support (TS), and personal best goals (PBGs) in different learning environments, specifically online classes and traditional physical classrooms. The research involved 84 participants divided into experimental (online classes, N = 41), and control (physical classes, N = 43) groups. Questionnaires were administered before and after the treatment to assess the participants’ AR, motivation, TS, and PBGs. The data were analyzed using Chi-square tests, revealing significant differences in AR, motivation, and PBGs between the two groups after the treatment. Online classes were found to enhance AR, motivation, PBGs, and acknowledgment of TS compared to the physical environment. These results suggest that PBA can have a positive impact on students’ psychosocial variables and shed light on the potential benefits of online learning environments. The implications of the study are discussed, and suggestions for further research are provided.
Exploring Elinor Ostrom's principles for collaborative group working within a user-led project: lessons from a collaboration between researchers and a user-led organisation
Authors: Wheeler Bella , Williams Oli , Meakin Becki , Chambers Eleni , Beresford Peter , O’Brien Sarah , Robert Glenn
Published: January 2024

Background

Some research has been undertaken into the mechanisms that shape successful participatory approaches in the context of efforts to improve health and social care. However, greater attention needs to be directed to how partnerships between researchers and user-led organisations (ULOs) might best be formed, practiced, managed, and assessed. We explored whether political economist Elinor Ostrom’s Nobel prize winning analysis of common pool resource management—specifically eight principles to enhance collaborative group working as derived from her empirical research—could be usefully applied within a user-led project aiming to co-design new services to support more inclusive involvement of Disabled people in decision-making processes in policy and practice.

Methods

Participant observation and participatory methods over a 16-month period comprising observational notes of online user-led meetings (26 h), online study team meetings (20 h), online Joint Interpretive Forum meetings (8 h), and semi-structured one-to-one interviews with project participants (44 h) at two time points (months 6 and 10).

Results

Initially it proved difficult to establish working practices informed by Ostrom’s principles for collaborative group working within the user-led project. Several attempts were made to put a structure in place that met the needs of both the research study and the aims of the user-led project, but this was not straightforward. An important shift saw a move away from directly applying the principles to the working practices of the group and instead applying them to specific tasks the group were undertaking. This was a helpful realisation which enabled the principles to become—for most but not all participants—a useful facilitation device in the latter stages of the project. Eventually we applied the principles in a way that was useful and enabled collaboration between researchers and a ULO (albeit in unexpected ways).

Conclusions

Our joint reflections emphasise the importance of being reflexive and responsive when seeking to apply theories of collaboration (the principles) within user-led work. At an early stage, it is important to agree shared definitions and understanding of what ‘user-led’ means in practice. It is crucial to actively adapt and translate the principles in ways that make them more accessible and applicable within groups where prior knowledge of their origins is both unlikely and unnecessary.
The effect of macronutrient and micronutrient supplements on COVID-19: an umbrella review
Authors: SeyedAlinaghi SeyedAhmad , Shahidi Ramin , Mojdeganlou Hengameh , Akhtaran Fatemeh Khajeh , Maroufi Seyed Farzad , Maroufi Seyede Parmis , Mirzapour Pegah , Karimi Amirali , Khodaei Sepideh , Pour Mehrzad Mohsseni , Mehraeen Esmaeil , Dadras Omid
Published: January 2024

Background and aims

A healthy diet play an important role in the prevention and even treatment of various diseases. Proper nutrition plays an important role in boosting of immune system. These include the consumption of macronutrients such as proteins, lipids, carbohydrates, and also micronutrients including vitamins. Here, we aimed to systematically review the effects of macronutrients and micronutrients on the prevention and treatment of COVID-19.

Methods

We searched the databases of PubMed, Scopus, Embase, and Web of Science on December 23, 2023. The records were downloaded into an EndNote file, the duplicates were removed, and the studies underwent a two-phase screening process based on their title/abstracts and full texts. The included articles were screened and underwent inclusion and exclusion criteria. We included the English systematic reviews and meta-analyses that concurred with the aim of our study. The selected articles were assessed by Cochrane's Risk of Bias in Systematic Reviews for the quality check. The data of the eligible studies were extracted in a pre-designed word table and were used for the qualitative synthesis.

Results

A total of 28 reviews were included in this study. Most studies have shown that micronutrients are effective in morbidity and mortality controlling in viral respiratory infections such as COVID-19 but some studies have shown that micronutrients are sometimes not effective in controlling severity. On the other hand, calcifediol was by far the most successful agent in reducing intensive care needs and mortality between studies.

Conclusion

Individuals without malnutrition had a reduced risk of SARS-CoV-2 infection and severe disease. The administration of Vitamin D is effective in reducing the morbidity and mortality of COVID-19 patients. Patients with vitamin D deficiency were more prone to experience severe infection, and they were at higher risk of morbidities and mortality. Other micronutrients such as Vitamin A, Vitamin B, and Zinc also showed some benefits in patients with COVID-19. Vitamin C showed no efficacy in COVID-19 management even in intravenous form or in high doses.
Toxicological analyses of the venoms of Nigerian vipers Echis ocellatus and Bitis arietans
Authors: Dingwoke Emeka John , Adamude Fatima Adis , Salihu Aliyu , Abubakar Mujitaba Suleiman , Sallau Abdullahi Balarabe
Published: January 2024

Background

Among the medically important snakes in Nigeria, Echis ocellatus and Bitis arietans have the most lethal venom. These venoms were classified according to the presence of snake venom metalloproteinases (SVMPs), snake venom phospholipase A2 (PLA2s), and snake venom serine proteases (SVSPs). Toxicological analyzes were performed to understand the significance of different protein families in venoms.

Methods

Proteins were separated from venom using column chromatography. The skin and footpad of mice were used to determine hemorrhagic and edematogenic activities. Caprine blood plasma was used to test fibrinolytic activity in vitro.

Results

The results showed that, compared to the crude venom, the SVMP fraction induced hemorrhagic effects with a diameter of 26.00 ± 1.00 mm in E. ocellatus and 21.33 ± 1.52 mm in B. arietans. Both SVSP and SVMP had anticoagulant effects; however, the SVSP fraction had a stronger effect, with a longer anticoagulation time of 30.00 ± 3.00 min in E. ocellatus and 26.00 ± 2.00 min in B. arietans. These main venom toxins, SVMPs, SVSPs, and PLA2, were found to have edema-forming effects that were optimal at 2 h after envenomation. PLA2s had the highest edema-inducing activity, with onset 30 min after envenomation.

Conclusions

Given the importance of SVMPs in altering the integrity of the membrane structure and impairing the blood coagulation system, an antivenom that can specifically neutralize its activity could inhibit the hemorrhage effects of the venoms.
Midwest prairie management practices benefit the non-target prairie crayfish
Authors: Bloomer Caitlin C. , Miller Christopher M. , DiStefano Robert J. , Taylor Christopher A.
Published: January 2024

Background

Prescribed burning is used to duplicate natural, pre-settlement prairie successional processes. It is an essential and commonly used tool to promote and protect biodiversity and enhance ecosystem function in tallgrass prairie remnants throughout the midwestern United States. The responses to prescribed burns vary widely among faunal groups. We conducted the first study into the response of the prairie crayfish (Procambarus gracilis Bundy) to periodic prescribed burns and other management activities in a tallgrass prairie in Northern Missouri. This species relies on natural and restored prairies across its broad distribution, but little is known on how to actively manage these populations.

Results

We found that the density of the prairie crayfish burrows did not vary in response to the burn regime; however, other management activities like the installation of artificial ponds for amphibians and reptiles were directly benefitting this species. Observations indicate that prairie crayfish may also show positive associations with warm-season grass stands and vegetation management should be further explored.

Conclusions

The current prairie management practices for vegetation, quail, and herpetofauna are having beneficial or neutral effects on non-target taxa like the prairie crayfish. The value of crayfish and their burrows in prairies is well-established. Conservation biologists should continue to examine how burrowing crayfish are responding to management practices for other taxa to explicitly manage and promote these populations.
Multicriteria decision-making tool for investigating the feasibility of the green roof systems in Egypt
Authors: Desouki Mahmoud , Madkour Mai , Abdeen Ahmed , Elboshy Bahaa
Published: January 2024

Urbanization in Egypt detracts from green spaces, reduces the per capita green ratio, and increases adverse effects such as heat islands, air pollution, and energy consumption. In addition, it affects social human comfort issues. In this context, building rooftops is a potential solution that could reduce the impact of green space scarcity. Such a solution has multiple evidence-based environmental, economic, and social benefits. Consequently, numerous governmental and private initiatives have spread the rooftop greening concept in Egypt. These initiatives have adopted several planting systems, such as soil-based, deep-water culture, and nutrient film technique systems. This manuscript examines these prevalent systems through environmental, economic and social lenses. This paper pioneers a user-centric tool to facilitate the system selection that aligns with individual needs. An analysis was conducted to ascertain the value of various factors influencing system choice, encompassing a literature review, expert opinion solicitation, market survey, and energy simulation. The Analytical Hierarchy Processes methodology was proposed to appraise the factors, aiding in arriving at an informed decision. The paper presents a novel contribution by studying many factors spanning diverse scientific domains. Furthermore, creating an accessible decision-support tool encapsulates a substantial addition to the body of knowledge.
Preoperative management using Impella support for acute aortic dissection with left coronary malperfusion: a case report
Authors: Shojima Takahiro , Takagi Kazuyoshi , Saku Kosuke , Fukuda Tomofumi , Tayama Eiki
Published: January 2024

Background

Acute aortic dissection (AAD) with impaired perfusion of the left coronary artery has a poor prognosis, even after urgent radical aortic surgery, due to extensive myocardial damage. Although Impella, a microaxial-flow catheter pump, is useful in managing acute myocardial infarction, it is generally contraindicated in patients with AAD because it is an intra-aortic device and the aortic structure is compromised in these cases. Here, we introduce a novel intervention that allowed a planned aortic repair after managing circulation using Impella and venoarterial extracorporeal membrane oxygenation in a case of AAD with left main trunk malperfusion.

Case presentation

A 40-year-old man presented with cardiogenic shock. Percutaneous coronary intervention was performed to address left main trunk obstruction using an intra-aortic balloon pump; however, circulatory instability persisted. The patient was transferred to our hospital after venoarterial extracorporeal membrane oxygenation. Impella CP™ was used to improve his circulatory status. However, a subsequent CT scan confirmed an AAD diagnosis. After 5 days of stable circulatory support, the patient underwent aortic root replacement and coronary artery bypass grafting.

Conclusions

In patients with AAD and coronary malperfusion, adjunctive circulatory management with Impella may be a valuable therapeutic option.
Three cases of diagnostic delay of type A acute aortic dissection
Authors: Shimamoto Takeshi , Tomotsuka Sanae , Takehara Makoto , Tsumaru Shinichi
Published: January 2024

Background

Diagnostic delay (DD) can be lethal when patients with type A acute aortic dissection (TAAAD). We report 3 cases of DD associated with TAAAD.

Case presentation

Case 1 is a female in her sixties presenting with severe back pain. A CT scan was taken, and TAAAD with a thrombosed false lumen was suspected by the radiology technician. He did not successfully transfer his concern to the physicians and the patient was sent home. The next day, she was transferred to another hospital with a recurrence of the symptom, and the diagnosis of TAAAD was made with a CT scan there. Case 2 was an 87-year-old female who was transferred to our hospital because of a loss of consciousness and bruises on the forehead. CT scan was taken and the displaced intimal flap in her aortic arch was overlooked by the part-time physician almost at the end of his shift. The diagnosis of TAAAD was made by the radiologist. Case 3 was the 44-year-old male who did not have health insurance and experienced severe back pain a few days before the visit to our clinic. On that day, he went to the nearby hospital’s emergency room, and only pain medication was prescribed. A few days later, a CT scan was taken at our hospital to investigate the cause of pyuria and the diagnosis of TAAAD was made.

Conclusion

DD may be common and multifactorial in our practice. Physicians need to take every step to improve diagnostic accuracy.
Cardiovascular biomarkers: exploring troponin and BNP applications in conditions related to carbon monoxide exposure
Authors: Taghdiri Andia
Published: January 2024

Background

The diagnosis and prognosis of cardiovascular disorders are greatly aided by cardiovascular biomarkers. The uses of troponin and B-type natriuretic peptide in situations involving carbon monoxide exposure are examined in this narrative review. These biomarkers are important because they help predict outcomes in cardiovascular disorders, track the effectiveness of therapy, and influence therapeutic choices.

Main body

Clinical practice makes considerable use of B-type natriuretic peptide (BNP), which has diuretic and vasodilatory effects, and troponin, a particular marker for myocardial injury. Carbon monoxide (CO) poisoning is a major worldwide health problem because CO, a “silent killer,” has significant clinical consequences. Higher risk of cardiac problems, poorer clinical outcomes, and greater severity of carbon monoxide poisoning are all linked to elevated troponin and B-type natriuretic peptide levels. BNP’s adaptability in diagnosing cardiac dysfunction and directing decisions for hyperbaric oxygen therapy is complemented by troponin’s specificity in identifying CO-induced myocardial damage. When combined, they improve the accuracy of carbon monoxide poisoning diagnoses and offer a thorough understanding of cardiac pathophysiology.

Conclusions

To sum up, this review emphasizes the importance of troponin and B-type natriuretic peptide (BNP) as cardiac indicators during carbon monoxide exposure. While BNP predicts long-term cardiac problems, troponin is better at short-term morbidity and death prediction. When highly sensitive troponin I (hsTnI) and B-type natriuretic peptide are combined, the diagnostic accuracy of carbon monoxide poisoning patients is improved. One of the difficulties is evaluating biomarker levels since carbon monoxide poisoning symptoms are not always clear-cut. Accurate diagnosis and treatment depend on the investigation of new biomarkers and the use of standardized diagnostic criteria. The results advance the use of cardiovascular biomarkers in the intricate field of carbon monoxide exposure.
Adding merits of vacuum assisted biopsy in diagnosis and management of indeterminate breast micro-calcifications
Authors: Moustafa Amr Farouk Ibrahim , Emam Mohamed Mohsen , Mokhtar Omnia , Ibraheem Maher Hassan , Mohammed Ghada , Gomaa Mohamed Mohamed Mohamed
Published: January 2024

Background

Stereotactic guided biopsies have become the sampling method of choice in diagnosis of non-palpable breast microcalcifications which directly impact patients’ management plans and consequently morbidity and mortality.

Purpose

The purpose is to compare the diagnostic accuracy of VAB and CNB in diagnosis of indeterminate breast microcalcifications and subsequent management of cases of indeterminate breast micro-calcifications.

Methods

Retrospective review of stereotactic CNB and VAB was done, pathological data were classified as benign, high risk and malignant lesions and compared with gold standard surgical specimen. The influence on patients’ surgical planning was depicted.

Results

A total of 268 lesions were included in our study divided as 136 lesions that underwent VAB and 132 lesions that underwent CNB, for the VAB group the overall PPV was 100% (96–100% CI) and NPV was 95.8% (90–98% CI) with overall diagnostic accuracy of 97% (92–99% CI), while for the CNB group the PPV was 100% (95–100% CI) and NPV was 80.2% (74.2–85% CI) with overall diagnostic accuracy of 84.8% (77–90% CI). 4/136 VAB lesions did not match the surgical specimen malignant diagnosis this could be explained by their mean diameter of 9.725 ± 1.8 cm and 3.172 ± 1.84 cm which was found statistically significant P value of less than 0.0001. The percentage of re-operation in VAB group was 2.9% while in CNB group was 7.5%.

Conclusions

VAB is a superior diagnostic tool over CNB in diagnosis of indeterminate breast microcalcifications and reducing the percentage of re-operations which directly impacts the patient’s morbidity. Moreover, it can replace surgery in cases of benign lesions and totally resected high risk lesions especially when operations are contraindicated or refused by the patient, yet with strict follow up.
Splenic artery aneurysm rupture in a pregnant woman with hepatosplenic schistosomiasis: case report and literature review
Authors: Razafindrazoto Chantelli Iamblaudiot , Randrianiaina Antsa Fihobiana , Ralaizanaka Behoavy Mahafaly , Rakotoniaina Henintsoa , Randriamifidy Nitah Harivony , Rasolonjatovo Anjaramalala Sitraka , Rakotozafindrabe Andry Lalaina Rinà , Rabenjanahary Tovo Harimanana , Razafimahefa Soloniaina Hélio , Ramanampamonjy Rado Manitrala
Published: January 2024

Background

Pregnancy is not uncommon in patients with non-cirrhotic portal hypertension. Rupture of a splenic artery aneurysm remains a rare complication, associated with a very poor maternal–fetal prognosis. Our aim is to report a case of ruptured splenic aneurysm and to show the maternal–fetal over-risks during the association of pregnancy and portal hypertension, even in non-cirrhotic patients.

Case presentation

We report a case of a 34-year-old woman, pregnant at 24 weeks gestation, with non-cirrhotic portal hypertension due to hepatic schistosomiasis. She was hospitalized for variceal bleeding. Patient had undergone endoscopic variceal band ligation and no bleeding recurrence. An unexplained hypovolemic shock appeared during the hospitalization with the occurrence of an in utero fetal death. The fetus was delivered by vaginal delivery. Abdominal CT scan angiogram showed a splenic artery aneurysm rupture. The patient underwent an emergency laparotomy with ligation of the splenic artery associated with splenectomy. Postoperative course was simple. Management of portal hypertension was continued at discharge (diuretic, beta-blockers, and esophageal varices ligation).

Conclusion

The association of pregnancy and portal hypertension remains a serious situation with a high risk of maternal–fetal complications. Splenic artery aneurysm rupture is one of the rare complications of this association with a very poor maternal–fetal prognosis. Open repair is the surgical treatment of choice with a non-negligible morbi-mortality.
Assessment of potential drug–drug interaction knowledge, attitude, and practice among Egyptian hospital and community pharmacists: a cross-sectional multicenter study
Authors: Wahsh Engy A. , Warda Ahmed E. Abou , Abdallah Mahmoud S. , Elsayed Aya , Daiem Yasser Soliman Abdel , Sadek Eman Mohamed
Published: January 2024

Background

Pharmacists have an important role in preventing prescribing errors and providing appropriate information. They can detect potential drug–drug interactions (DDIs), which are associated with a more extended hospital stay and higher medical costs that lead to substantial financial burdens on healthcare systems. This study aimed to evaluate and assess the knowledge of community and hospital pharmacists toward drug–drug interaction and their attitude and motivation to find DDI information, in addition to identifying the pharmacist factors affecting this knowledge. A cross-sectional multicenter study was conducted using a self-administered questionnaire. Nineteen drug pairs, that are common in clinical practice, were evaluated. This study aimed to evaluate and assess the knowledge of community and hospital pharmacists toward drug–drug interaction and their attitude and motivation to find DDI information, in addition to identifying the pharmacist factors affecting this knowledge.

Results

A total of 4363 pharmacists (2260 community pharmacists and 2103 hospital pharmacists) have completed the survey. The participants' knowledge of DDIs was 58.25%, and there was no significant difference in pharmacist knowledge between community and hospital pharmacists (p = 0.834). The highest correct answer was for sildenafil and isosorbide mononitrate pair 78.8%. The most used source of information was the internet or mobile applications, 47.1%. Participants who always considered PDDIs while prescribing detected more drug interactions than those who did not (p = 0.001).

Conclusion

According to the findings of this study, community and hospital pharmacists had comparable knowledge of DDIs. However, before dispensing uncommon prescriptions, they should consult evidence-based drug information resources and DDI software to identify potential drug interactions.
Adjuvant radiotherapy after curative resection of hepatocellular carcinoma with narrow margin (≤1 cm): A phase 2, multicenter, randomized controlled trial.
Authors: Ming Kuang , Peng Zhenwei , Chen Zebin , Shen Shunli , Li Bin
Published: January 2024

722

Background:
RAISE is a multicenter, randomized, open-label, parallel-group phase 2 trial, aiming to assess the efficacy and safety of intensity modulated radiation therapy (IMRT) compared with active surveillance in hepatocellular carcinoma (HCC) patients with narrow margin (≤ 1 cm) following curative resection.
Methods:
HCC patients with narrow margin were randomly assigned in a 1:1 ratio to receive either IMRT (Surgery-IMRT group) or active surveillance (Surgery group) after hepatectomy. Randomized stratification factors include tumor size (≤ 5 vs. > 5 cm) and microvascular invasion (presence vs. absence). In the Surgery-IMRT group, patients received IMRT within 1-3 months after surgical resection. The prescription dose was planned at 50-60 gray in 25-30 fractions over 5-6 weeks. The primary endpoint was recurrence free survival (RFS). The secondary endpoints were safety and overall survival (OS). The planned sample size was 148 patients in total to obtain an improvement in the 2-year RFS rate from 45% to 65%, to detect a hazard ratio (HR) of 0.54, with a one-sided alpha of 5% and 80% power.
Results:
Between January 15, 2019, and September 15, 2023, 148 patients from 6 hospitals in China were randomized: 74 patients were allocated to the Surgery-IMRT group and 74 to the Surgery group. The median follow-up duration was 27.4 months (95% confidence interval [CI] 23.2-29.2 months). The 2-year RFS was 78.37% (95% CI 64.35%–87.40%) for the Surgery-IMRT group and 57.43% (95% CI 43.25%–69.28%) for the Surgery group (P=0.028). The median OS was not reached for the two groups. The following radiotherapy-related grade 3–4 adverse events were 3 thrombocytopenia, 3 neutropenia, and 1 hemoglobin decreased.
Conclusions:
In conclusion, this trial showed that the adjuvant IMRT following curative resection can bring survival benefits of RFS for HCC patients with narrow margin. Clinical trial information: NCT03732105.
Longitudinal circulating tumor DNA monitoring for detection of molecular residual disease in patients with penile squamous cell carcinoma.
Authors: Patel Mukti , Tan Alan
Published: January 2024

11

Background: Penile squamous cell carcinoma (SCC) is an extremely rare, aggressive disease, representing 0.4-0.6% of all malignancies in males in the U.S. and Europe. Early diagnosis is imperative, as lymphatic spread is associated with a dismal prognosis. The estimated 5-year survival rate in patients with pelvic lymph node involvement is 0%. Moreover, there are limited treatment options that carry significant toxicity risks. Accurate biomarkers to evaluate treatment response and guide treatment to improve outcomes are needed. Molecular residual disease monitoring with circulating tumor DNA (ctDNA) may be helpful in these scenarios. Methods: This is a retrospective analysis of a cohort of 7 patients with advanced HPV-unassociated penile SCC treated at Rush University Medical Center who monitored closely for molecular residual disease (MRD). Signatera (Natera Inc.), a personalized tumor-informed ctDNA assay, was utilized for detection and quantification of ctDNA in patients’ plasma samples, measured at regular intervals. Progression of disease was based on radiographic imaging. Results: In our cohort, personalized, tumor-informed ctDNA assays were designed for 100% (7/7) of the patients. ctDNA was detectable in at least one time point in all of the patients. One patient underwent partial penectomy and lymph node (LN) dissection with 1/11 LN involved. He is being monitored without adjuvant treatment and has sustained ctDNA clearance. Another patient underwent surgery, and had positive post-operative ctDNA. He was treated with adjuvant TIP (paclitaxel, ifosfamide, and cisplatin) with subsequent ctDNA clearance. In 3 of the patients, ctDNA was checked at regular intervals and rising ctDNA prompted imaging studies that showed progression. These patients proceeded to second line treatment options. The remaining 2 patients are non-surgical candidate with LN positivity, who will begin treatment with TIP and monitoring of ctDNA after each cycle of chemotherapy. Twenty-eight percent (2/7) of patients remain alive with sustained ctDNA clearance. Twenty-eight percent (2/7) of patients remain alive with ctDNA positivity, planned to initiate treatment and monitoring of ctDNA at regular intervals. Forty-three percent (3/7) of patients who had persistent ctDNA positivity are now deceased. Conclusions: Our data suggests that a personalized, tumor-informed ctDNA assay is not only useful for MRD monitoring, but also highly predictive of treatment response and imaging-based progression in patients with penile SCC. In our sample, MRD status correlated with both radiographic progression and clinical outcomes. Prospective studies are needed to better understand how ctDNA can be used to guide neoadjuvant and adjuvant approaches, including treatment intensification or de-escalation, in patients with penile SCC.
Maintenance of patient-reported quality of life (EQ-5D-3L) post neoadjuvant relugolix prior to the initiation of prostate radiation therapy.
Authors: Koh Min Ji , Koh Min Jung , Hsueh Jessica , Gallagher Lindsey , Danner Malika , Zwart Alan , Ayoob Marilyn , Yung Thomas M. , Kumar Deepak , Carrasquilla Michael , Leger Paul Denis , Dawson Nancy Ann , Suy Simeng , Collins Sean P.
Published: January 2024

117

Background: Injectable GnRH receptor agonists have been shown to improve cancer control when combined with radiotherapy (RT) for unfavorable intermediate- to high-risk prostate cancer. Relugolix is a new oral GnRH receptor antagonist that achieves high rates of rapid profound castration (total testosterone < 20 ng/dL), which may impact health-related quality of life. This prospective study sought to evaluate the impact of neoadjuvant relugolix on health-related quality of life in prostate cancer patients prior to the start of prostate RT. Methods: Patients treated at Georgetown between May 2021 and August 2023 with neoadjuvant relugolix (at least 2 months prior to RT) per an institutional protocol were included in the study (IRB 12-1775). The 5-item EQ-5D-3L, a validated questionnaire that assesses the patient-reported health status outcome, was collected for each patient at baseline (before relugolix initiation) and one hour prior to RT initiation. EQ VAS Score Overall ranges from 0-100 with a higher score indicating better quality of life. Individual items including mobility, self-care, usual activities, pain/discomfort, and anxiety/depression were scored on a three-point scale from 1 (No problems) to 3 (Extreme). To examine changes before and after relugolix treatment, McNemar’s test and paired samples t-test were used. Minimally important difference (MID) calculated by 0.5 of standard deviation at baseline was used to examine clinical significance. Results: Of 79 patients, the median age was 73 years, and 42% were non-white. Patients initiated relugolix at a median of 4 months prior to questionnaire administration (IQR: 3.9-5.4), at which most (95%) patients achieved castration (≤ 50 ng/dL). The VAS Score Overall was significantly higher at baseline (Mean ± SD: 83 ± 10) than the paired score at the start of RT (80 ± 14, p = 0.01). This change was not clinically significant. There were no statistically or clinically significant differences in any of the 5 individual items. Conclusions: Neoadjuvant relugolix prior to prostate radiation therapy did not clinically significantly affect patient-reported quality of life. Also, there was no statistically significant decrease in each of the 5 individualized items evaluating health-related quality of life. Future studies should focus on comparing it to GnRH agonist-induced change in quality of life. [Table: see text]
PETRANHA: Phase 1/2 study of AZD5305 + novel hormonal agents in patients with metastatic prostate cancer–Interim safety and pharmacokinetic results.
Authors: Azad Arun , Voskoboynik Mark , Joshua Anthony M. , Weickhardt Andrew James , Sankey Peter , Pacey Simon , Heath Elisabeth I. , Krieger Laurence , Horvath Lisa , Pilié Patrick Glen , Womersley Lynsey , Linardopoulos Spiros , Moorthy Ganesh , Zhou TJ , Brown Jessica , de Paula Bruno , Lukacs Edit , Hudson Andrew
Published: January 2024

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Background: The combination of PARP inhibitors (PARPi) with novel hormonal agents (NHAs) has recently demonstrated significant improvement in progression-free survival in patients (pts) with metastatic castration-resistant prostate cancer (mCRPC) compared with NHAs alone. AZD5305, a PARP1-selective inhibitor, has the potential for an improved safety profile and limited drug-drug interactions (DDIs) compared with first-generation PARPi. PETRANHA, an open-label nonrandomized study, is evaluating the safety and DDIs of AZD5305 with physician’s choice of NHA (enzalutamide [enza], abiraterone acetate [abi] or darolutamide [daro]) in pts with metastatic prostate cancer. Methods: Pts were aged ≥18 years with histologically confirmed mCRPC or metastatic castration-sensitive prostate cancer (mCSPC), suitable for NHA treatment, with or without HRR mutations in tumor tissue. Key exclusion criteria were previous PARPi, platinum chemotherapy, or targeted radioligand therapy for pts with mCRPC or mCSPC; and previous NHA or docetaxel in pts with mCSPC. Pts were assigned to receive AZD5305 60 mg once daily (OD; first dose level tested) and either enza 160 mg OD (Arm 1), abi 1000 mg + 5 mg prednisone OD (Arm 2), or daro 600mg twice daily (Arm 3) until disease progression or any intolerable adverse event (AE) occurred. Primary objectives were safety and tolerability. DDIs were evaluated for each combination. Results: At data cutoff (July 10, 2023), 48 pts were included in the interim safety analysis (Arm 1, n=11; Arm 2, n=19; Arm 3, n=18). In total, 32 (66.7%) pts had mCRPC, 16 (33.3%) pts had mCSPC, and 8 (16.7%) pts were pre-exposed to NHAs. Median duration of AZD5305 exposure was 6.3 months (range, 1.05–12.58) across all arms. Safety data are presented in the Table. The most common AEs were anemia (52.1%; Gr ≥3, 16.7%), fatigue (50.0%; Gr ≥3, 2.1%), and neutropenia (33.3%; Gr ≥3, 6.3%). No dose-limiting toxicities or AE-related deaths occurred in any arm; AEs leading to discontinuations were uncommon. No clinically significant DDIs were measured with any of the combinations. Conclusions: Initial safety, tolerability, and DDI data from the PETRANHA study indicates that AZD5305 can be safely combined with three individual NHAs with low rates of dose interruptions or reductions. The study is ongoing in Australia, Italy, UK, and USA. Clinical trial information: NCT05367440 . [Table: see text]
Association of prior poly(ADP-ribose) polymerase (PARP) inhibitor therapy with response to 177Lu-PSMA-617 (LuPSMA) in men with DNA damage repair (DDR) mutations.
Authors: Raychaudhuri Ruben , Mo George , Moradi Tuchayi Abuzar , Graham Laura , Gulati Roman , Pritchard Colin C. , Haffner Michael C. , Yezefski Todd , Hawley Jessica E. , Montgomery Robert Bruce , Cheng Heather H. , Nelson Peter , Chen Delphine L , Hope Thomas A. , Iravani Amir , Schweizer Michael Thomas
Published: January 2024

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Background: LuPSMA, a radioligand therapy targeting the cell surface protein PSMA, is approved for men with PSMA-positive mCRPC previously treated with androgen receptor signaling inhibitor (ARSI) and taxane chemotherapy. Several PARP inhibitors (PARPi) are also currently approved for patients with mCRPC harboring alterations in genes associated with DNA damage repair (DDR). Given that both therapeutics result in DNA damage, we hypothesized that there would be clinical evidence of cross-resistance between the two classes of agents, with decreased efficacy in patients receiving LuPSMA following a PARPi. Methods: We abstracted retrospective data from patients at three centers who received at least one cycle of LuPSMA per the FDA label and had panel-based tumor sequencing performed. Patients with PARPi qualifying mutations were included in the analysis. PSA50 responses (i.e. ≥50% decline in PSA from baseline), PSA progression free survival (PFS) and overall survival (OS) following treatment with LuPSMA were compared between patients who received prior PARPi (PARPi-T cohort) and those who did not (PARPi-NT cohort). Results: Forty-nine patients with a PARPi qualifying alteration who received at least one cycle of LuPSMA were identified. Baseline characteristics (Gleason score, visceral metastases, race, ECOG PS, PSMA SUVmean/max) were similar between cohorts. Prior non-PARPi lines of therapy, including receipt of radium-223 (14% vs 21%), carboplatin (33% vs 36%), ≥ 2 prior ARSI (67% vs 68%), and ≥ 2 prior taxanes (43% vs 47%) were also similar between the PARP-NT and PARP-T cohorts respectively. Median PSA PFS and OS were both significantly increased in the PARPi-NT cohort as compared to the PARPi-T cohort (Table). PSA50 responses were numerically increased in the PARP-NT cohort, although this did not reach statistical significance. The most common PARPi qualifying alteration was BRCA2 (N=15). PARP-NT patients with BRCA2 alterations had significantly increased PSA PFS and OS as well as PSA50 response rates compared to the PARP-T patients. Conclusions: Prior receipt of PARPi therapy appears to negatively associate with the clinical activity of LuPSMA, with the largest difference in outcomes observed in patients with BRCA2 mutations. These data support the hypothesis that PARPi therapy may lead to clinically significant cross-resistance with LuPSMA. Prospective studies to evaluate the optimal sequence of LuPSMA and PARPi therapy are justified. [Table: see text]
Comparison of adverse event rate of prostate-specific membrane antigen (PSMA)-targeted radionuclide therapy (TRT) with antibody or small molecule ligand targeting vector.
Authors: Ruder Samuel Francis , Sun Michael Philip , Thomas Charlene , Molina Ana M. , Nauseef Jones T. , Osborne Joseph , Sternberg Cora N. , Nanus David M. , Bander Neil Harrison , Tagawa Scott T.
Published: January 2024

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Background: PSMA-targeted radionuclide therapy (PSMA-TRT) has been established with use of either monoclonal antibodies (mAb) or small molecule ligands (SML) as the targeting vectors for delivery of 177Lu to PSMA-expressing prostate cancer. mAb and SML differ in their molecular weight, pharmacokinetics, and biodistribution which is predicted to result in different adverse effect profiles. Methods: In this study with written informed consent, we compare the adverse effects from individual patients receiving PSMA-TRT for mCRPC using mAb (J591) vs SML (PSMA-617 or PSMA I&T) for delivering 177Lu in prospective clinical trials or registry. All-grade treatment-emergent adverse events (TEAEs) were extracted from trial databases. Adverse effects were graded 0-5. Pearson’s Chi-squared test was used to assess TEAEs and association with treatment type. Multivariable logistic regression was used to compare TEAEs after adjusting for administered radioactivity dose and CALGB (Halabi) prognostic score. Results: 248 patients with mCRPC were treated from March 2001 to February 2023. 166 (67.7%) received mAb (177Lu-J591), 81 received SML [76 (30.6%) 177Lu-PSMA-617, 5 (2%) 177Lu-PSMA-I&T)]. The median age was 70.9 years (44.5 yrs to 93.8 yrs). At the time of trial enrollment, 137 (55.2% [68% SML and 49% mAb]) patients had exposure to chemotherapy, 112 (45.1%) had exposure to androgen-receptor pathway therapy, 193 (77.8%) had bone metastases, 120 (48.3%) LN mets, 42 (16.9%) lung mets, and 20 (8.0%) liver mets. 142 (57.2%) had Halabi score high disease. All-grade hematologic TEAEs were more common with mAb: neutropenia in 122 (74%) patients vs 16 (20%) (p<0.001), anemia in 122 (73%) vs 26 (33%) (P<0.001), and thrombocytopenia in 145 (87%) vs 25 (32%) (p<0.001). Gr >3 neutropenia occurred in 79 (47%) and Gr >3 thrombocytopenia in 98 (59%) receiving mAb. All-grade non-hematologic TEAEs were generally more common with SML: fatigue in 31 (53%) vs 79 (48%) (p=0.5), pain in 32 (54%) vs 73 (44%) (p=0.2), nausea in 21 (36%) vs 34 (20%) (p=0.02) and xerostomia in 36 (61%) vs 1 (0.6%) (p<0.001). After adjusting for administered dose and Halabi score, treatment with 177Lu via SML vector was associated with less neutropenia (OR 0.04, 95% CI 0.02-0.09, p<0.001), anemia (OR 0.11, 95% CI 0.06-0.22, p<0.001), and thrombocytopenia (OR 0.04, 95% CI 0.02-0.09, p<0.001) but more nausea (OR 3.2, 95% CI 1.54-6.72, p=0.002) and xerostomia (NA due to low event rate in mAb). Conclusions: As predicted, PSMA-TRT with mAb vs SML is associated with different toxicity profiles. PSMA-TRT with the mAb 177Lu-J591 is more commonly associated with hematologic toxicities compared to the SML 177Lu-PSMA-617 and 177Lu-PSMA-I&T, which are more commonly associated with non-hematologic toxicities.
The prognostic value of ductal adenocarcinoma of the prostate in patients with advanced prostate cancer treated with abiraterone acetate.
Authors: Shi Yifu , Wei Xinyuan , Zhao Fengnian , Zhao Jinge , Shen Pengfei , Chen Ni , Zeng Hao
Published: January 2024

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Background: Previous studies have indicated that ductal adenocarcinoma of the prostate (DA) is associated with adverse prognosis in patients with localized prostate cancer (PCa). However, the clinical significance of DA in advanced PCa remains largely ambiguous. This study endeavors to investigate the relationship between the existence of DA in prostate biopsy specimens and treatment outcomes among patients with advanced PCa receiving abiraterone acetate (AA) therapy. Methods: We retrospectively analyzed data from 440 patients with advanced PCa who received AA at either the metastatic hormone-sensitive (mHSPC, N=123) or castration-resistant PCa (mCRPC, N=317) stage. The presence of DA and its proportion was evaluated based on prostate biopsy specimens. Kaplan-Meier curves and COX regression were used to evaluate the predictive significance of DA on AA efficacy, including PSA response, PSA progression-free survival (PSA-PFS), and radiographic progression-free survival (rPFS). Results: In aggregate, DA was detected in 35/440 (8.0%) patients, with 13/440 (3.0%) and 22/440 (5.0%) men harboring DA<5% and ≥5%, respectively, in the total tumors. The overall PSA response rate in the entire cohort was 302/440 (68.6%), and it was comparable for people with and without DA, with both groups having a response rate of 68.6%. Of note, compared with patients without DA, men with DA have significantly longer median PSA-PFS (mPSA-PFS, 12.1- vs. 25.0-Mo, P=0.005) and median rPFS (mrPFS, 19.8 vs. 38.2-Mo, P=0.034). Subgroup analysis based on DA proportion further revealed that in comparison with PCa without DA, DA≥5% was an indicator of favorable PSA-PFS (HR, 95%CI: 0.28, 0.14-0.56, p<0.001) and rPFS (HR, 95%CI: 0.35, 0.18-0.72, p=0.004), while DA<5% was not. In multivariate COX regression analysis, after adjusting by clinicopathological factors, including mCRPC/mHSPC stage, ISUP grading, metastatic burden, pain score and pretreatment hemoglobin, alkaline phosphatase, and lactate dehydrogenase, DA≥5% was still independently associated with better therapeutic efficacy of AA treatment (PSA-PFS: HR, 95%CI: 0.36, 0.17-0.74, p<0.001; rPFS: HR, 95%CI: 0.47, 0.23-0.96, p=0.040). Conclusions: A DA proportion ≥5% in the tumor is related to improved treatment efficacy for individuals with advanced PCa receiving AA. Thus, in the pathological diagnosis of PCa, it is necessary to routinely report the presence and proportion of DA in order to aid with treatment decision-making.