Dose escalation of tolinapant (ASTX660) in combination with standard radical chemoradiotherapy in cervical cancer : a study protocol for a phase 1b TiTE-CRM clinical trial (CRAIN) in UK secondary care centres.

BACKGROUND: Cervical cancer is the fourth most common cancer in women, with an estimated 342,000 deaths worldwide in 2020. Current standard of care in the UK for locally advanced cervical cancer is concurrent chemoradiotherapy with weekly cisplatin, yet 5-year overall survival rates are only 65% with a distant relapse rate of 50%. Inhibitors of Apoptosis Proteins (IAPs) are often overexpressed in cancer cells and associated with tumour progression and resistance to treatment. Tolinapant, developed by Astex Pharmaceuticals, is an IAP antagonist with an additional mechanism of action via down-regulation of NF-kB, an important regulator in cervical cancer. Preclinical studies performed using tolinapant in combination with cisplatin and radiotherapy showed inhibition of tumour growth and enhanced survival. There is therefore a strong rationale to combine tolinapant with chemoradiotherapy (CRT). METHODS: CRAIN is a phase Ib open-label, dose escalation study to characterise the safety, tolerability and initial evidence for clinical activity of tolinapant when administered in combination with cisplatin based CRT. Up to 42 patients with newly diagnosed cervix cancer will be recruited from six UK secondary care sites. The number of participants and the duration of the trial will depend on toxicities observed and dose escalation decisions, utilising a TiTE-CRM statistical design. Treatment will constist of standard of care CRT with 45 Gy external beam radiotherapy given in 25 daily fractions over 5 weeks with weekly cisplatin 40mg/m2. This is followed by brachytherapy for which common schedules will be 28 Gy in 4 fractions high-dose-rate or 34 Gy in 2 fractions pulsed-dose-rate. Tolinapant will be administered in fixed dose capsules taken orally daily for seven consecutive days as an outpatient on alternate weeks (weeks 1, 3, 5) during chemoradiation. Dose levels for tolinapant which will be assessed are: 60 mg; 90 mg (starting level); 120 mg; 150 mg; 180 mg. Escalation will be guided by emerging safety data and decisions by the Safety Review Committee. DISCUSSION: If this trial determines a recommended phase II dose and shows tolinapant to be safe and effective in combination with CRT, it would warrant future phase trials. Ultimately, we hope to provide a synergistic treatment option for these patients to improve outcome. TRIAL REGISTRATIONS: EudraCT Number: 2021-006555-34 (issued 30th November 2021); ISRCTN18574865 (registered 30th August 2022).

La práctica de la evaluación del riesgo de violencia en España / The practice of violence risk assessment in Spain

Antecedentes. La valoración del riesgo de violencia es un requisito fundamental en la toma de decisiones profesionales que implican prevenir, intervenir o informar sobre la conducta de las personas. El uso de herramientas estructuradas de evaluación del riesgo de violencia ha mostrado mejoría en la precisión de las evaluaciones basadas exclusivamente en el juicio clínico o en la pericia de un experto en contextos psiquiátricos, penitenciarios y jurídicos. Objetivo. Este estudio presenta los resultados de la primera encuesta sobre las prácticas profesionales asociadas al uso de herramientas de evaluación del riesgo de violencia en España. Materiales y métodos. La información fue recogida mediante la administración de una encuesta en internet que fue distribuida por correo electrónico a los miembros de organizaciones profesionales. Resultados. De manera similar a los contextos profesionales del resto del mundo, las escalas de psicopatía de Robert Hare (Psychopathy Checklist-Revised y Psychopathy Checklist: Screening Version) y el Historical-Clinical-Risk Management-20 encabezaron la lista de las herramientas más usadas tanto por elección personal como por requisito institucional. Conclusiones. Se ofrecen datos novedosos sobre la prevalencia de uso y la utilidad percibida de las herramientas estructuradas, así como sobre otras cuestiones relacionadas a las prácticas profesionales de evaluación del riesgo de violencia en España que pueden orientar tanto a los profesionales de contextos sanitarios, correccionales y forenses, como a los responsables de las instituciones en la elección de las herramientas a implementar para asistirlos en la toma de decisiones.

Background. Violence risk assessment is a key requirement in professional decision making involving prevention, intervention or reporting on human behavior. The use of structured tools for violence risk assessment has shown to improve the accuracy of assessments based exclusively on clinical judgment or expertise in psychiatric, correctional and legal settings. Objectives. This study presents results of the first survey about professional practices associated with tools for violence risk assessment in Spain. Materials and methods. The information was collected by administering an online-based survey that was distributed by e-mail to members of professional organizations around the country. Results. As in professional contexts worldwide, the Robert Hare's psychopathy scales (Psychopathy Checklist-Revised and Psychopathy Checklist: Screening Version) and the Historical-Clinical-Risk Management-20 topped the list of the most used tools both by professional choice and institutional requirement. Conclusions. We provide novel data on the prevalence of use and the perceived utility of specific tools, as well as on other issues related to the professional practice of violence risk assessment in Spain, which can guide professional in the health care, correctional and forensic settings, as well as those responsible for decisions in institutions about choosing which tool to implement.

Mitotic quiescence, but not unique "stemness," marks the phenotype of bone metastasis-initiating cells in prostate cancer.

This study aimed to identify subpopulations of prostate cancer cells that are responsible for the initiation of bone metastases. Using rapidly dividing human prostate cancer cell lines, we identified mitotically quiescent subpopulations (<1%), which we compared with the rapidly dividing populations for patterns of gene expression and for their ability to migrate to the skeletons of athymic mice. The study used 2-photon microscopy to map the presence/distribution of fluorescently labeled, quiescent cells and luciferase expression to determine the presence of growing bone metastases. We showed that the mitotically quiescent cells were very significantly more tumorigenic in forming bone metastases than fast-growing cells (55 vs. 15%) and had a unique gene expression profile. The quiescent cells were not uniquely stem cell like, with no expression of CD133 but had the same level expression of other putative prostate stem cell markers (CD44 and integrins α2/ß1), when compared to the rapidly proliferating population. In addition, mitotic quiescence was associated with very high levels of C-X-C chemokine receptor type 4 (CXCR4) production. Inhibition of CXCR4 activity altered the homing of quiescent tumor cells to bone. Our studies suggest that mitotic dormancy is a unique phenotype that facilitates tumor cell colonization of the skeleton in prostate cancer.

Comparing nurses' and doctors' prescribing habits.

BACKGROUND: Nurses' prescribing activity in a mental health trust prompted examination of whether nurse prescribers replicate their mentors' prescribing habits. AIM: To explore nurses' and medical mentors' prescribing habits to inform nurse-prescribing strategy. METHOD: The trust's 14 most-active nurse prescribers and nine of their medical mentors were interviewed. Transcripts underwent phenomenological analysis. RESULTS: 64 themes emerged showing nurses and doctors approach prescribing differently. Themes were grouped into four categories. DISCUSSION: Nurse prescribers tend to have greater holistic awareness of patients but are also more risk averse. CONCLUSION: Greater strategic vision is required to incentivise nurse prescribing; on its current trajectory it will not meet identified prescribing needs.

Internalization and biodistribution of polymersomes into oral squamous cell carcinoma cells in vitro and in vivo.

The prognosis for oral squamous cell carcinoma (OSCC) is not improving despite advances in surgical treatment. As with many cancers, there is a need to deliver therapeutic agents with greater efficiency into OSCC to improve treatment and patient outcome. The development of polymersomes offers a novel way to deliver therapy directly into tumor cells. Here we examined the internalization and biodistribution of two different fluorescently labeled polymersome formulations; polyethylene oxide (PEO)-poly 2-(diisopropylamino)ethyl methacrylate (PDPA) and poly 2-(methacryloyloxy)ethyl phosphorylcholine (PMPC)-PDPA, into SCC4 OSCC cells in vitro and in vivo. In vitro SCC4 monolayers internalized PMPC-PDPA and PEO-PDPA at similar rates. However, in vivo PMPC-PDPA polymersomes penetrated deeper and were more widely dispersed in SCC4 tumors than PEO-PDPA polymersomes. In the liver and spleen PMPC-PDPA mainly accumulated in tissue macrophages. However, in tumors PMPC-PDPA was found extensively in the nucleus and cytoplasm of tumor cells as well as in tumor-associated macrophages. Use of PMPC-PDPA polymersomes may enhance polymersome-mediated antitumor therapy.

Intimate partner abuse of older men: considerations for the assessment of risk.

Intimate partner abuse among older persons, though less common than among the general population, is a significant concern. Drawing from the intimate partner abuse and elder abuse literatures, this paper presents considerations for the assessment of risk for intimate partner abuse perpetrated against older men, with reference to the prevalent gendered view of abuse between intimate partners. Potential victim and perpetrator risk factors specific to this context are discussed and existing risk assessment tools are introduced. Implications and future research directions are discussed with regard to the application of risk assessment technology to this context.

The effects of torture-related injuries on long-term psychological distress in a Punjabi Sikh sample.

Torture survivors often report chronic debilitating physical and psychological distress. Prior research on the relationship between physical and psychological trauma suggests that the 2 are not independent. Injury sustained during torture may increase the likelihood of subsequent distress as either a moderator or mediator. For long-term psychopathology in a sample of Punjabi Sikh survivors of human rights violations (N = 116), chronic injuries mediated the path between torture and posttraumatic stress disorder, specifically the severity of numbing symptoms. Although injuries were associated with major depression, torture was not, and injuries did not moderate the relationship between major depression and torture. Chronic injuries may represent trauma severity or persistent traumatic cues. These findings emphasize connections between physical and psychological trauma and the importance of an interdisciplinary approach to torture treatment.

Gray, black, and blue: the state of research and intervention for intimate partner abuse among elders.

Though not as common as in younger populations, intimate partner abuse (IPA) among elders is a significant and often overlooked problem. In this article, we focus on problems for research and intervention. We begin with a brief review of the phenomena of elder abuse and IPA, highlighting problems resulting from definitional issues and inconsistencies in research methodology. The balance of the paper comprises a discussion of problems for intervention. Drawing from the IPA and elder abuse literatures, risk factors unique to IPA among elders are presented, and limitations of existing screening and risk assessment instruments for use within this context are identified. The focus then shifts to legal considerations when working with elders who have experienced or perpetrated IPA. Our goals are to synthesize the elder abuse and IPA literatures, identify limitations within both, and to reflect upon the state of knowledge regarding IPA among elders.

The subjective experience of trauma and subsequent PTSD in a sample of undocumented immigrants.

Although a subjective component of trauma is commonly recognized in diagnosing posttraumatic stress disorder (PTSD), there are few studies that specifically address Criterion A2, and none addressing this issue among undocumented immigrants. We assessed 212 arriving undocumented immigrants with diverse trauma histories to investigate concordance between objective and subjective factors of trauma (Criteria A1 and A2) and across different types of trauma and PTSD. Concordance between Criteria A1 and A2 varied, with highest rates found for political violence. Interpersonal violence in general was associated with higher rates of PTSD. We identified a dose-response effect for PTSD, but this was not dependent on other events (i.e., other doses) meeting Criterion A2. Discussion focuses on Criterion A within the phenomenology of PTSD and the need to gauge subjective interpretations of trauma events among this population.