bluuebunny/crossref_metadata_2025 huggingface dataset:
“My motivation was to save”: a qualitative study exploring factors influencing motivation of community healthcare workers in a cervical cancer screening program in Dschang, Cameroon
Authors: Hämmerli Pauline , Moukam Alida Datchoua , Wisniak Ania , Sormani Jessica , Vassilakos Pierre , Kenfack Bruno , Petignat Patrick , Schmidt Nicole Christine
Published: June 2022

Background

Cervical cancer is a major public health issue among women in Cameroon and uptake of screening programs remains a challenge in many low- and middle-income countries. Community healthcare workers can play an important role in promoting cervical cancer services. This study aimed to explore factors affecting the motivation of community healthcare workers in a cervical cancer screening program in Dschang, Cameroon.

Methods

A qualitative approach including 11 in-depth individual interviews with community healthcare workers was used. The interviews were audio-recorded, transcribed and coded using thematic analysis assisted by ATLAS.ti software.

Results

Four women and seven men aged between 21 and 77 years old were interviewed. Community healthcare workers had high motivation. Factors affecting motivation were divided into individual and environmental level, based on a theoretical framework. Factors with a positive influence on motivation were mainly on the individual side while impeding factors were mainly associated with the environmental level.

Conclusions

Key interventions to improve motivation among community healthcare workers include: (i) more training and supportive supervision; (ii) evaluation of remuneration systems by workload; and (iii) provision of job-enabling resources such as uniforms, cellphone cards and transport.

Trial registration:Geneva Cantonal Ethics Committee on Human Research (No. 2017-01110) and the Cameroonian National Ethics Committee for Human Health Research (No. 2018/07/1083/CE/CNERSH/SP).
Personal beliefs and social norms regarding the sexual exploitation of girls in age-disparate transactional sexual relationships in Brazil: a mixed-methods study
Authors: Ignacio Caroline Ferraz , Cerdeira Linda , Cislaghi Beniamino , Lauro Giovanna , Buller Ana Maria
Published: June 2022

Background

In the global debate around transactional sex little attention has concentrated on Brazil, despite ranking fourth globally in absolute number of girls married or co-habiting by the age of 15 years, and evidence showing that these unions often begin as age-disparate transactional sex (ADTS). This article contributes to filling this gap by exploring the personal beliefs and social norms related to ADTS in urban (favela) communities of Rio de Janeiro, Brazil between adult men (> 18 years) and girls and adolescents (G/A) (< 18 years) with a minimum 5-year age disparity. The primary objective of this study was to identify the social norms that promote and prevent ADTS, and the dynamics between individual beliefs and social norms, to provide contextualized recommendations to prevent ADTS in this setting.

Methods

An exploratory, sequential, mixed-methods design was used, starting with a qualitative phase that included semi-structured, in-depth interviews and focus groups, and a subsequent quantitative phase comprising of a community survey. The items for the quantitative questionnaires were developed based on the qualitative results.

Results

Mixed methods results indicate that in these communities ADTS is normalised and not considered exploitative. We identified three themes related to the reasons ADTS occurs: girls’ responsibility, male desires and benefits of ADTS. Men’s role in ADTS was largely minimised because of a general acceptance of a notion of masculinity characterised by hypersexuality and lack of impulse control. Individual beliefs, however, did not tend to align with these social norms.

Conclusions

In this study, personal beliefs and social norms often did not align, suggesting that initiatives working to change personal or attitudes regarding ADTS may not lead to meaningful change in ADTS behaviours, and social norms interventions may be more effective. Our findings reinforce the need to develop programs tailored to local understandings of ADTS, targeting not only girls but also a wide range of actors. Interventions could also consider the structural factors acting in local and global contexts that promote or prevent ADTS.
Systems analysis and improvement approach to optimize outpatient mental health treatment cascades in Mozambique (SAIA-MH): study protocol for a cluster randomized trial
Authors: Cumbe Vasco F. J. , Muanido Alberto Gabriel , Turner Morgan , Ramiro Isaias , Sherr Kenneth , Weiner Bryan J. , Flaherty Brian P. , Sharma Monisha , Faduque Flávia , Xerinda Ernesto Rodrigo , Wagenaar Bradley H.
Published: June 2022

Background

Significant investments are being made to close the mental health (MH) treatment gap, which often exceeds 90% in many low- and middle-income countries (LMICs). However, limited attention has been paid to patient quality of care in nascent and evolving LMIC MH systems. In system assessments across sub-Saharan Africa, MH loss-to-follow-up often exceeds 50% and sub-optimal medication adherence often exceeds 60%. This study aims to fill a gap of evidence-based implementation strategies targeting the optimization of MH treatment cascades in LMICs by testing a low-cost multicomponent implementation strategy integrated into routine government MH care in Mozambique.

Methods

Using a cluster-randomized trial design, 16 clinics (8 intervention and 8 control) providing primary MH care will be randomized to the Systems Analysis and Improvement Approach for Mental Health (SAIA-MH) or an attentional placebo control. SAIA-MH is a multicomponent implementation strategy blending external facilitation, clinical consultation, and provider team meetings with system-engineering tools in an overall continuous quality improvement framework. Following a 6-month baseline period, intervention facilities will implement the SAIA-MH strategy for a 2-year intensive implementation period, followed by a 1-year sustainment phase. Primary outcomes will be the proportion of all patients diagnosed with a MH condition and receiving pharmaceutical-based treatment who achieve functional improvement, adherence to medication, and retention in MH care. The Consolidated Framework for Implementation Research (CFIR) will be used to assess determinants of implementation success. Specific Aim 1b will include the evaluation of mechanisms of the SAIA-MH strategy using longitudinal structural equation modeling as well as specific aim 2 estimating cost and cost-effectiveness of scaling-up SAIA-MH in Mozambique to provincial and national levels.

Discussion

This study is innovative in being the first, to our knowledge, to test a multicomponent implementation strategy for MH care cascade optimization in LMICs. By design, SAIA-MH is a low-cost strategy to generate contextually relevant solutions to barriers to effective primary MH care, and thus focuses on system improvements that can be sustained over the long term. Since SAIA-MH is integrated into routine government MH service delivery, this pragmatic trial has the potential to inform potential SAIA-MH scale-up in Mozambique and other similar LMICs.

Trial registration

ClinicalTrials.gov; NCT05103033; 11/2/2021.
Thoracoscopic resection of posterior mediastinal paraganglioma: perioperative management and surgical tips
Authors: Matsumura Yuki , Fukuhara Mitsuro , Tanabe Hayato , Yamaguchi Hikaru , Takagi Hironori , Ozaki Yuki , Muto Satoshi , Okabe Naoyuki , Shio Yutaka , Suzuki Hiroyuki
Published: June 2022

Posterior mediastinal paraganglioma (PM-PGL) is a rare disease that is difficult to diagnose. If PM-PGL is misdiagnosed preoperatively, surgeons may encounter severe tachycardia and hypertension and easy bleeding from the tumor during the operation. Therefore, it is essential to include PGL as a differential diagnosis for mediastinal tumors. We herein describe a 73-year-old Japanese man with a PM-PGL that was diagnosed preoperatively and resected safely by video-assisted thoracic surgery. Preoperative management of hypertension with doxazosin mesylate, soft coagulation of the peritumor area, and careful clipping of feeding arteries were effective for hemostasis. The patient’s vital signs were stable during and after the operation.
Factors associated with children’s HIV- positive status disclosure in Wolaita Zone, Southern Ethiopia: a cross-sectional study
Authors: Walle Belete Gelaw , Tiruneh Chalie Marew , Dessie Tigabu , Selomon Nigusie , Kassaw Amare , Chekole Bogale , Wubneh Moges , Lankrew Tadele , Bayih Wubet Alebachew
Published: June 2022

Background

Children’s HIV-positive status disclosure is an essential component of chronic care & long-term disease management. The modalities of status disclosure are complex and vary across different communities. Although data from various settings are necessary to overcome this problem, evidence is limited, specifically in the in the study areas. Therefore, this study aimed to assess the prevalence of HIV-positive status disclosure and associated factors among children on antiretroviral therapy (ART).

Methods

A mixed-method, facility-based study was conducted: among 203 caregivers with children in Wolaita Zone, Southern Ethiopia. We used in-depth interviews for qualitative data in addition to structured questionnaires. Simple random sampling for quantitative and purposive sampling for qualitative parts was applied. We used Content or Thematic analysis for qualitative and Binary logistic regression for quantitative.

Results

All the caregivers were interviewed and majorities (84.7%) of them were female. One hundred twelve children (55.2%) were below 12 years of age. In this study, the overall prevalence of children with HIV-positive status disclosure was 46.8%. Being 12 or more years of age (AOR = 7.5, 95% CI: 2.9–15.6), duration on ART 72 or more months (AOR = 3.8, 95% CI: 1.7–6.7), death of the parent (AOR = 2.0, 95% CI: 1.1- 3.8), and having follow up in the hospital (AOR = 2.1, 95% CI: 1.3–4.7) were associated with disclosure. Being an immature child was the commonest reason cited by caregivers for non-disclosure. Frequent questions by the child about why they are taking drugs, for better self-care, and treatment adherence were the commonest reason of caregivers for disclosing their children’s HIV-positive status.

Conclusion

In our study, children’s HIV-positive status disclosure was significantly low. This study identified different factors (Health facility, children, and caregivers-related factors) as the main reason for disclosing children’s HIV-positive status. Hence, health care workers should give special attention to children’s HIV-positive status disclosure, which helps to increase the effectiveness of treatment and prevent further HIV transmission.
Clinical trial registration during COVID-19 and beyond in the African context: what have we learned?
Authors: Mathebula Lindi , Runeyi Sinazo , Wiysonge Charles , Ndwandwe Duduzile
Published: June 2022

Since the outbreak of COVID-19, many lives have been impacted especially on the African continent which is already fighting the burden of multiple diseases of poverty. However, clinical research has offered hope for treatment and prevention options for this infectious disease. Despite many COVID-19 clinical trials conducted globally, three countries in Africa account for more than 80% of all trials from the continent registered trials in clinical trial registries. This indicates geographic disparity among COVID-19 research in Africa. From the perspective of clinical trial registration, transparency in clinical research and the availability of data became important for making informed decisions to manage the pandemic. Registries serve as a source of planned, ongoing, and completed trials while allowing efficient funding allocation for research that would not duplicate efforts. Additionally, research gaps can be identified, which provide opportunities for collaboration among researchers. Therefore, a critical lesson learnt during this pandemic is that clinical trial registration is important in facilitating the process of tracking changes made to protocols and minimizing publication bias, thereby promoting and advocating for clinical research transparency. Moreover, registration in a clinical trial registry is a condition for publication and allows for trial summary results to be publicly available. Adhering to the principle of results sharing is especially important for the rapidly growing clinical research activities racing to find evidence-based interventions to end the COVID-19 pandemic.
Unpacking the ‘black box of horrendousness’: a qualitative exploration of the barriers and facilitators to conducting trials involving adults lacking capacity to consent
Authors: Shepherd Victoria , Hood Kerenza , Wood Fiona
Published: June 2022

Background

Trials involving adults who lack capacity to consent encounter a range of ethical and methodological challenges, resulting in these populations frequently being excluded from research. Currently, there is little evidence regarding the nature and extent of these challenges, nor strategies to improve the design and conduct of such trials. This qualitative study explored researchers’ and healthcare professionals’ experiences of the barriers and facilitators to conducting trials involving adults lacking capacity to consent.

Methods

Semi-structured interviews were conducted remotely with 26 researchers and healthcare professionals with experience in a range of roles, trial populations and settings across the UK. Data were analysed using thematic analysis.

Results

A number of inter-related barriers and facilitators were identified and mapped against key trial processes including during trial design decisions, navigating ethical approval, assessing capacity, identifying and involving alternative decision-makers and when revisiting consent. Three themes were identified: (1) the perceived and actual complexity of trials involving adults lacking capacity, (2) importance of having access to appropriate support and resources and (3) need for building greater knowledge and expertise to support future trials. Barriers to trials included the complexity of the legal frameworks, the role of gatekeepers, a lack of access to expertise and training, and the resource-intensive nature of these trials. The ability to conduct trials was facilitated by having prior experience with these populations, effective communication between research teams, public involvement contributions, and the availability of additional data to inform the trial. Participants also identified a range of context-specific recruitment issues and highlighted the importance of ‘designing in’ flexibility and the use of adaptive strategies which were especially important for trials during the COVID-19 pandemic. Participants identified a need for better training and support.

Conclusions

Researchers encountered a number of barriers, including both generic and context or population-specific challenges, which may be reinforced by wider factors such as resource limitations and knowledge deficits. Greater access to expertise and training, and the development of supportive interventions and tailored guidance, is urgently needed in order to build research capacity in this area and facilitate the successful delivery of trials involving this under-served population.
Seasonal dynamics of Amblyomma sculptum: a review
Authors: de Paula Luiza Gabriella Ferreira , do Nascimento Rafael Moreira , Franco Artur de Oliveira , Szabó Matias Pablo Juan , Labruna Marcelo Bahia , Monteiro Caio , Krawczak Felipe da Silva
Published: June 2022

Background

Amblyomma sculptum is a hard tick that is associated with domestic animals and the transmission of Brazilian spotted fever. This association has motivated several field studies on this ixodid tick within its distribution area in South America. Thorough knowledge of the seasonal dynamics of A. sculptum in different ecological scenarios is required in order to better understand the biological characteristics of this tick and develop techniques for the control and prevention of diseases transmitted by this vector. In this article, we systematically review the seasonal dynamics of A. sculptum and tick collection methodology.

Methods

A systematic search of the Scopus, Web of Science, PubMed and Scielo databases was carried out for articles (including dissertations and theses) on the population dynamics of A. sculptum. The inclusion criterion was the report of seasonal dynamic studies on A. sculptum through surveys carried out for at least 1 year with, as methodology, tick collection in the environment and/or tick count/collection on A. sculptum primary hosts (horses or capybaras). Studies carried out before the reclassification of Amblyomma cajennense sensu lato in 2014, which referred to Amblyomma cajennense in areas where it is currently known that only A. sculptum occurs, were also included. Articles meeting the inclusion criterion, but not available in online databases, were also added based on the authors’ experience on the subject. Sixteen articles and one thesis were selected for inclusion in this systematic review.

Results

Most of the studies were carried out in the southeastern region of Brazil, with a few also carried out in the northeast, center-west and south of Brazil and northwest of Argentina. Five techniques/methods were applied across these studies: CO2 traps, dragging, flagging, visual searches and tick counting on animals, used alone or in combination.

Conclusion

Seasonal dynamics of A. sculptum was found to be similar in almost all of the areas studied, with larvae predominating during the autumn, nymphs in the winter and adults in the spring and summer.

Graphical abstract
Medicinal plant use, conservation, and the associated traditional knowledge in rural communities in Eastern Uganda
Authors: Ssenku Jamilu E. , Okurut Shaban A. , Namuli Aidah , Kudamba Ali , Tugume Patience , Matovu Paul , Wasige Godfrey , Kafeero Hussein M. , Walusansa Abdul
Published: June 2022

Background

The global consumption of herbal medicine is increasing steadily, posing an extinction risk to medicinal plants. Uganda is among the top ten countries with a high threat of herbal medicine extinction, and Traditional Medicinal Knowledge (TMK) erosion. This might be attributed to the inadequate documentation, plus many more unclear hindrances. In this study, plant species used to treat human diseases in Butaleja district in Eastern Uganda and their associated TMK were documented. The conservation methods for medicinal plants were also evaluated. The rationale was to support the preservation of ethnopharmacological knowledge.

Methods

Data were collected from 80 herbalists using semi-structured questionnaires, from July 2020 to March 2021. Additionally, guided field walks and observations were conducted. Quantitative indices such as, use categories and informant consensus factor (ICF) were evaluated to elucidate the importance of the medicinal plants. Data were analyzed using STATA version-15.0 software.

Results

In total, 133 species, belonging to 34 families and 125 genera were identified. Fabaceae (65%), and Solanaceae (29%) were the dominant families. Leaves (80%), and roots (15%), were the commonest parts used in medicinal preparations; mostly administered orally as decoctions (34.6%) and infusions (16%). The commonest illnesses treated were cough (7.74%), gastric ulcers (7.42%), and malaria (4.52%). The informant consensus factor was high for all disease categories (≥ 0.8), indicating homogeneity of knowledge about remedies used. Only 73% of the respondents made efforts to conserve medicinal plants. The commonest conservation strategy was preservation of forests with spiritually valued species (100%), while compliance with government regulations was the rarest (4.5%). Overall, efforts to stop the extinction of medicinal plants and TMK were inadequate.

Conclusion and recommendations

There was enormous dependency on a rich diversity of medicinal plant species and TMK for healthcare and income generation. The potential for medicinal plant biodiversity loss was evident due to habitat destruction. Inclusion of traditional cultural norms in conservation strategies, and laboratory-based efficacy tests for the species identified are necessary, to promote the conservative and utilization of validated herbal medicines and TMK in rural settings.
A qualitative exploration of the contributions of Polio Eradication Initiative to the Nigerian health system: policy implications for polio transition planning
Authors: Akinyemi Oluwaseun , Adebayo Adedamola , Bassey Christopher , Nwaiwu Chioma , Kalbarczyk Anna , Nomhwange Terna , Alonge Olakunle O. , Owoaje Eme T.
Published: June 2022

Background

The Nigerian health care system is weak due to lack of coordination, fragmentation of services by donor funding of vertical services, dearth and poor distribution of resources, and inadequate infrastructures. The Global Polio Eradication Initiative has supported the country’s health system and provided strategies and skills which need to be documented for use by other health programs attempting disease control or eradication. This study, therefore, explored the contributions of the Polio Eradication Initiative (PEI) activities to the operations of other health programs within the Nigerian health system from the perspectives of frontline workers and managers.

Methods

This cross-sectional qualitative study used key informant interviews (KIIs) and inductive thematic analysis. Twenty-nine KIIs were conducted with individuals who have been involved continuously in PEI activities for at least 12 months since the program's inception. This research was part of a more extensive study, the Synthesis and Translation of Research and Innovations from Polio Eradication (STRIPE), conducted in 2018. The KII tool focused on four major themes: work experience in other health programs, similarities and differences between polio programs and other health programs, contributions of polio programs, and missed opportunities for implementing polio lessons. All interviews were transcribed verbatim and analyzed using a thematic framework.

Results

The implementation of the PEI has increased health promotion activities and coverage of maternal and child health interventions through the development of tangible and intangible resources, building the capacities of health workers and discovering innovations. The presence of a robust PEI program within a weakened health system of similar programs lacking such extensive support led to a shift in health workers' primary roles. This was perceived to reduce human resources efforts in rural areas with a limited workforce, and to affect other programs' service delivery.

Conclusion

The PEI has made a notable impact on the Nigerian health system. There should be hastened efforts to transition these resources from the PEI into other programs where there are missed opportunities and future control programs. The primary health care managers should continue integration efforts to ensure that programs leverage opportunities within successful programs to improve the health of the community members.
Neuropathy and neurocognitive impairment in long-term survivors of pediatric cancer treated without central nervous system (CNS) directed therapy.
Authors: Williams AnnaLynn , Phillips Nicholas Steve , Goodenough Chelsea Goodliffe , Brinkman Tara M. , Papini Chiara , Jacola Lisa M , Delaney Angela M. , Armstrong Gregory T. , Jefferies John L. , Khan Raja B. , Robison Leslie L. , Hudson Melissa M. , Ness Kirsten K. , Krull Kevin R.
Published: June 2022

10020

Background: Survivors of pediatric cancer, including those without CNS-directed treatment, are at risk of neurocognitive impairment and peripheral or autonomic neuropathies; conditions that co-occur in non-cancer populations. Using the St. Jude Lifetime Cohort, we investigated associations between these sequelae to inform contributors to long-term cancer-related neurocognitive impairment. Methods: Clinically assessed survivors of pediatric cancer (N=2,138, mean age 31 [SD 13], 23[11] years from diagnosis, 51% male) not treated with CNS-directed therapy completed neurocognitive testing. Modified total neuropathy score peripheral sensory and motor subscales were combined with functional tasks and severity graded using a modified NCI CTCAE. Cardiac autonomic neuropathy was defined as impaired heart rate reserve (<80% age- sex-predicted or ≤62% with beta blocker). Separate log binomial regression models estimated risk of neurocognitive impairment (age adjusted z-score <10th percentile) associated with grade 2+ sensory, motor or autonomic neuropathy. Path analysis examined if pain with daily interference mediated associations between motor or sensory neuropathy and neurocognitive impairment. Results: 838 (39%) survivors had autonomic, 115 (5.4%) had motor and 162 (7.6%) had sensory neuropathy. Compared to those with no neuropathy, survivors with motor or sensory neuropathy had a higher risk of impairment in sustained attention, visual-motor processing speed, short- and long-term memory, and executive function (Table, p’s<0.01). Autonomic neuropathy was associated with a higher risk of impairment in visuo-motor processing speed (p=0.03). Pain partially mediated associations between sensory neuropathy and sustained attention (10% mediated, p=0.04), visual-motor processing speed (8% p=0.02), and executive function (14% p=0.02). Pain was not related to motor neuropathy. Conclusions: Peripheral and autonomic neuropathies are associated with significant risk of neurocognitive impairment in adult survivors of pediatric cancer. Research is needed to further understand shared mechanisms (e.g., pain, inflammation) to design targeted interventions to improve neuropathic symptoms and neurocognitive function. [Table: see text]
ADVL1514, a phase 1 study of ABI-009 (nab-sirolimus) in pediatric patients with recurrent or refractory solid tumors, including CNS tumors as a single agent and in combination with temozolomide and irinotecan: A Children’s Oncology Group pediatric early-phase clinical trial network study.
Authors: Cramer Stuart , Gilger Elizabeth Ann , Burlingame Susan , Militano Olga , Liu Xiaowei , Minard Charles G. , Reddy Alyssa Terry , Voss Stephan D. , Berg Stacey L. , Reid Joel M. , Fox Elizabeth , Weigel Brenda
Published: June 2022

10022

Background: nab-Sirolimus (formerly know ABI-009 and nab-rapamycin) is a novel human albumin-bound preparation of sirolimus, a potent mTOR inhibitor. We report results of a Phase I study of ABI-009 alone and in combination with irinotecan and temozolomide in children with relapsed/refractory solid or CNS tumors. Methods: Patients (age 1-21 years) with relapsed/refractory solid or CNS tumors were eligible. Using a rolling 6 design, ABI-009 was administered intravenously as a single agent on Days 1 and 8 of cycle 1 (cycle = 21d), then subsequent cycles ABI-009 was administered in combination with temozolomide (125 mg/m2/dose, maximum 250 mg/dose) orally once daily x 5 on Days 1-5 and irinotecan 90 mg/m2/dose orally once daily x 5 on Days 1-5. Three dose levels (DL) of ABI-009 were investigated (DL1: 35mg/m2/dose, DL-1: 20mg/m2/dose, and DL-2: 15mg/m2/dose). The maximum tolerated dose (MTD) or Recommended Phase 2 Dose (RP2D) was established based on dose limiting toxicity (DLT) observed during Cycle 1 and 2. At the RP2D, additional patients were enrolled for pharmacokinetics (PK). Results: 33 patients were enrolled (32 eligible and 1 ineligible); 11 did not experience DLT but were not evaluable for toxicity due to progressive disease or physician decision to discontinue protocol therapy prior to completion of cycle 2; 17 [median age 13 (2-20) years] were evaluable for determination of MTD during dose escalation, 6 were enrolled on the PK cohort, of which 3 were evaluable to toxicity. At DL1, 2/5 patients experienced DLT (thrombocytopenia during cycle 1 (n = 1) and cycle 2 (n = 1)); at DL-1, 2/6 patients experienced DLT (thrombocytopenia in cycle 1); at DL-2, 1/6 patients experienced DLT (thrombocytopenia in cycle 1). PK expansion enrolled at DL-2 and 1/3 participants evaluable for toxicity had a DLT (mucositis). Overall, at DL-2, 2/9 patients (22%) had DLT. One patient with Ewing Sarcoma had a partial response and remained on study for 35 cycles; Patients (one each) with Ewing Sarcoma, Wilms Tumor, and Pineoblastoma had stable disease, ranging from 3-6 cycles. Conclusions: Thrombocytopenia was dose limiting for ABI-009 alone and in combination with temozolomide and irinotecan. The MTD for ABI-009 is 15mg/m2/dose days 1 and 8 in combination with 5 daily doses of temozolomide 125 mg/m2/dose and oral irinotecan 90 mg/m2/dose. One patient had a partial response, 3 patients had prolonged stable disease. Pharmacokinetics and pharmacodynamics are pending and will inform future trials. Clinical trial information: NCT02975882.
Impact of ribociclib (RIB) dose modifications (mod) on overall survival (OS) in patients (pts) with HR+/HER2- advanced breast cancer (ABC) in MONALEESA(ML)-2.
Authors: Hart Lowell L. , Bardia Aditya , Beck Joseph Thaddeus , Chan Arlene , Neven Patrick , Hamilton Erika P. , Sohn Joohyuk , Sonke Gabe S. , Bachelot Thomas , Spring Laura , Le Gac Fabienne , Hu Huilin , Gao Ming , De Laurentiis Michelino
Published: June 2022

1017

Background: The phase 3 ML-2, -3, and -7 trials all demonstrated consistent and statistically significant OS benefit with RIB (starting dose: 600 mg/d 3 wk on/1 wk off) vs PBO in pts with HR+/HER2− ABC. RIB dose mod (reductions and/or interruptions) when needed did not impact OS benefit with RIB + endocrine therapy (ET) in previous analyses of ML-3/-7. Here we present data on the effect of RIB dose mod on OS in postmenopausal pts with HR+/HER2− ABC in ML-2. Methods: ML-2 (NCT01958021) enrolled postmenopausal pts randomized 1:1 to first-line RIB + letrozole (LET) or PBO + LET. Landmark (LM) analyses of OS were performed to evaluate the association between dose reductions (yes vs no) and OS. Multiple LM times were considered to determine the sensitivity of the findings. As an alternative to LM analysis, a Cox proportional hazards model with a time-varying covariate was performed. Two time-dependent variables, dose reduction (with/without mod from 600 mg starting dose) and relative dose intensity 2 (RDI2), were included in the respective model as covariates to explore the association with OS. To account for differences in time to first dose mod, RDI2 reflects the post–dose mod period. Median (m) OS was obtained using a modified Kaplan-Meier method. Results: At data cutoff (June 10, 2021; m follow-up, 49.35 [range, 0-86.7] mo), 209 of 334 pts (62.6%) had ≥ 1 RIB dose reduction and 125 of 334 (37.4%) had 0 RIB dose reduction. LM analyses by dose reduction are presented (Table). mOS was 66.0 (95% CI, 57.6-75.7) mo in pts with ≥ 1 RIB dose reduction vs 60.6 (95% CI, 42.5-79.2) mo in pts with no RIB dose reductions (HR, 0.87 [95% CI, 0.65-1.18]). RDI2 was classified according to tertile: low (< 64.27%), medium (64.27%-95.86%), and high (> 95.86%). In pts with low, medium, and high RDI2, mOS was 62.6 (95% CI, 50.0-80.7) mo, 63.9 (95% CI, 48.8-not reached [NR]) mo, and 65.3 (95% CI, 50.5-NR) mo, respectively (HR low vs high, 0.99 [95% CI, 0.69-1.42]; HR medium vs high, 0.97 [95% CI, 0.62-1.38]). Conclusions: In this exploratory analysis of ML-2, OS benefit was maintained in pts with HR+/HER2− ABC who required mod from the recommended starting dose of RIB (600 mg/d 3 wk on/1 wk off). No relationship was observed between OS and RIB dose reduction or RDI2; OS benefit with RIB was observed in all groups. Clinical trial information: NCT01958021. [Table: see text]
Results from plasmaMATCH trial cohort E: A phase II trial of olaparib and ceralasertib in patients with triple-negative advanced breast cancer (CRUK/15/010).
Authors: Ring Alistair E. , Moretti Laura , Afshari-Mehr Angelica , Wardley Andrew M. , Kilburn Lucy , Gurel Bora , MacPherson Iain R. , Baird Richard D. , Martin Sue , Pearson Alex , Roylance Rebecca , Winter Matthew , Dunne Kathryn , Copson Ellen , Hickish Tamas , Stephens Peter , Burcombe Russell J. , Randle Katrina , Bliss Judith , Turner Nicholas C.
Published: June 2022

1024

Background: The plasmaMATCH trial was an open label platform trial, consisting of circulating tumour DNA (ctDNA) testing in ̃1000 patients with advanced breast cancer (ABC) linked to parallel treatment cohorts with therapies matched to mutations identified in ctDNA. Cohorts A-D have already reported (Turner N et al, Lancet Oncol 2020). Cohort E recruited patients with triple negative breast cancer (TNBC) without a targetable mutation identified at ctDNA screening, treating with olaparib (PARP inhibitor) plus ceralasertib (ATR inhibitor). Methods: Patients with TNBC who had received 1 or 2 lines of chemotherapy for advanced disease or relapsed within 12 months of (neo)adjuvant chemotherapy were eligible. Treatment was olaparib 300mg b.i.d continuously and ceralasertib 160mg qd on days 1–7 on a 28 day cycle, until disease progression. The primary endpoint was confirmed objective response rate by RECIST v1.1. Secondary endpoints included clinical benefit rate, progression-free survival (PFS) and safety. Biomarker analysis included response according to BRCA and somatic DNA repair gene status and ATM loss. Using a two-stage design with a target response rate of 25%, unacceptable response rate of 10%, alpha=2% and power=90%, ≥13 responses out of 69 evaluable stage 2 patients were required to infer efficacy (5/37 stage 1). Results: Between 17/09/18 and 5/10/20 75 patients enrolled in Cohort E of whom 70 were evaluable for response. The median age was 55.6 years. 42 (56%) patients had 1 and 13 (17.3%) had 2 prior line(s) of chemotherapy for metastatic disease. Efficacy is shown in Table. The most common grade ≥3 adverse events were: hypertension 12 (17%) and anaemia 9 (13%). Dose reductions and interruptions occurred in 19 (26.4%) and 34 (47.2%) patients respectively. Conclusions: The response rate to olaparib and ceralasertib did not meet pre-specified criteria for efficacy in the overall evaluable population. Responses were observed in patients without germline or somatic BRCA1/2 mutations. Translational analyses are underway to identify potential biomarkers of response in this population and will be presented at the meeting. Clinical trial information: ISRCTN16945804. [Table: see text]
Zanidatamab (zani), a HER2-targeted bispecific antibody, in combination with docetaxel as first-line (1L) therapy for patients (pts) with advanced HER2-positive breast cancer: Preliminary results from a phase 1b/2 study.
Authors: Lee Keun-Seok , Wang Xiaojia , Im Young Hyuck , Zeng Xiaohua , Li Huiping , Wang Kun , Li Huiyan , Zhou Ping , Bao Yuanyuan , Jiang Zefei
Published: June 2022

1031

Background: HER2-targeted agents have improved outcomes in HER2-positive breast cancer, but some pts develop resistance, relapse, or do not respond to current 1L therapies. Zani, also known as ZW25, is a novel HER2-targeted bispecific antibody that binds to two distinct extracellular domains of HER2. In a Phase 1 trial (NCT02892123) zani was well tolerated and demonstrated preliminary antitumor activity as monotherapy/with chemotherapy in pts with pre-treated advanced HER2+ breast cancer. Methods: Cohort 1 of this ongoing open-label, Phase 1b/2 study (NCT04276493) is evaluating zani in combination with docetaxel as a 1L therapy in adult females with advanced HER2+ breast cancer who may have received prior neoadjuvant/adjuvant treatment. Cohort A pts received zani 30 mg/kg IV, Cohort B pts received zani 1800 mg IV, both with docetaxel 75 mg/m2 IV Q3W. Primary endpoints were safety and investigator (INV)-assessed objective response rate (ORR) per RECIST v1.1. Secondary endpoints included INV-assessed duration of response (DoR), disease control rate (DCR) and progression-free survival (PFS). Results: As of Nov 26, 2021, 25 pts with a median age of 57.0 years (range: 33.0–80.0) were assigned to Cohort A (n=11) or B (n=14). Median study follow-up was 7.0 months (range: 1.1–17.4) and the median number of treatment cycles was 10 (range: 2–20), 16 (64.0%) pts remained on treatment. Of the 22-efficacy evaluable (EE) pts, confirmed ORR was 86.4% (95% CI: 65.1, 97.1). The 6 months PFS rate was 90.9% (95% CI: 68.3, 97.7). Efficacy data are summarized in Table 1. All pts experienced ≥ 1 treatment emergent adverse event (TEAE) and 17 (68.0%) pts experienced ≥ Grade 3 TEAEs. In total, 23 (92.0%) pts experienced treatment related TEAEs (trTEAEs), and 17 (68.0%) pts experienced ≥ Grade 3 trTEAEs. The most common trTEAEs were diarrhea (56.0%) and decreased neutrophil count (52.0%). Serious trTEAEs occurred in two (8.0%) pts, trTEAEs leading to treatment discontinuation occurred in one (4.0%) pt and no trTEAEs led to death. Conclusions: Zani and docetaxel combination demonstrated antitumor activity in 1L therapy for advanced HER2+ breast cancer, with a manageable safety profile. Clinical trial information: NCT04276493. [Table: see text]
Early clinical safety and pharmacokinetics data of DZD1516, an BBB-penetrant selective HER2 inhibitor for the treatment of HER2-positive metastatic breast cancer.
Authors: Hu Xichun , Zhang Jian , McAndrew Nicholas Patrick
Published: June 2022

1038

Background: Patients with HER2+ metastatic breast cancer (MBC) are at high risk of developing central nervous system metastases. DZD1516 is a reversible HER2-specific tyrosine kinase inhibitor (TKI) with full blood-brain barrier (BBB) penetration. Here we report the preliminary safety and PK data from the ongoing phase 1 study (NCT04509596) in patients with HER2+ MBC who relapsed from multiple prior treatments. Methods: Eligible patients received single oral dosing of DZD1516 on C0D1 and then twice daily (BID) oral dosing from C1D1 in a continuous 21-day cycle until disease progression, unacceptable toxicity or withdrawal of consent. The primary objective is to investigate the safety and PK of DZD1516 as a single agent. Results: As of 17 January 2022, DZD1516 was explored in 21 HER2+ MBC patients from the USA and China. DZD1516 was well tolerated at doses < 300 mg, BID. Two DLT events were reported in the 300 mg cohort. In all cohorts, 20 (95.2%) patients reported treatment-emergent adverse events (TEAEs), and 3 (14.3%) patients reported grade 3 drug-related TEAE. Two patients had dose interruption and one patient had dose reduction due to TEAE, all in the 300 mg cohort. Majority of TEAEs were reversible. The longest treatment duration was > 3 months. In all cohorts, the most common (> 20%) TEAEs included headache (42.9%), vomiting (38.1%), nausea (23.8%) and hemoglobin decreased (23.8%). At doses < 300 mg, there is no diarrhea or rash reported. PK data showed that combined exposure of DZD1516 and its active metabolite DZ2678 increased in a dose-proportional manner across the dose ranges. Elimination half-life was about 15-19 hrs. About 2-fold accumulation of DZD1516 in AUC was observed on multiple doses. In vitro, both DZD1516 and DZ2678 showed good permeability, and were not substrates of P-gp and BCRP. In patients, Kpuu,CSF of DZD1516 and DZ2678 was around 2.13 and 0.66, respectively, suggesting good CNS penetration. At the time of data cutoff, 16 patients had at least one post treatment anti-tumor assessment. With a median of 7 lines of prior treatment, the best anti-tumor response was stable disease. Conclusions: Preliminary clinical data showed that DZD1516 is a full BBB-penetrant HER2 TKI, with good safety profile. Consistent with its high selectivity, no wide type EGFR related AEs have been reported. Further evaluation of its safety and efficacy is ongoing. Clinical trial information: NCT04509596. [Table: see text]
Prognostic implications of HER2Neu-low in metastatic breast cancer.
Authors: Hasan Shaakir , Neubauer Zachary , Press Robert H. , Chhabra Arpit , Fox Jana Lauren , Cahlon Oren , Bakst Richard Lorne , Simone Charles B. , Choi J. Isabelle
Published: June 2022

1044

Background: HER2-Low (or HER2-equivocal, FISH negative) breast cancer has historically been treated as HER2-negative; however, recent evidence suggests that there may be prognostic and/or predictive differences between the two. We explore demographic characteristics and clinical outcomes of HER2-negative and HER2-low metastatic breast cancer (MBC) patients using real world data. Methods: We queried the National Cancer Database to identify MBC patients that were HER2 0, HER2 1+, or HER2 2+ per immunohistochemical staining, with the latter two defined as HER2-low and the former HER2-negative. A multivariable binomial regression analysis identified demographic and clinical correlates of each subtype. A Cox multivariable regression analysis (MVA), propensity matched to HER2 status, was performed to identify correlates of survival. Results: After excluding missing data, 24,636 MBC patients diagnosed between 2008-2015 were identified, 6,865 (27.9%) of whom were HER2-negative and 17,771(72.1%) of whom were HER2-low. There were no differences between the two groups with respect to age, race, year treated, location, income, insurance status, Charles Deyo comorbidity score, laterality, T stage, N stage, or use of systemic therapy. HER2-low tumors were half as likely to have concomitant hormone receptor-negative status (OR = 0.49, 95% CI 0.46-0.53). The 3-year survival rate among hormone receptor-negative patients was 33.8% for HER2-low and 32.2% for HER2-negative, and 60.9% and 55.6% in HER2-low and HER2-negative cases among hormone receptor-positive patients, respectively. HER2-low cases were associated with better survival on MVA (HR = 0.91, 95% CI 0.87-0.95), and remained superior with propensity-matching (HR = 0.92, 95% CI 0.89-0.96). In a subset analysis isolated to hormone receptor-positive cases, HER2-low remained correlated with improved survival (HR = 0.93, 95% CI 0.89-0.98) with propensity-matched MVA. Correlates of worse survival include older age as a continuous variable (HR = 1.02), Black race (HR = 1.13), uninsured (HR = 1.18), comorbidity score > 0 (HR = 1.28), higher T stage (HR = 1.17 to 2.34), node positivity (HR = 1.17) and, as the most influential, hormone receptor-negative status (HR = 1.94) [all P < 0.01]. Conclusions: Consistent with recent data in non-MBC, our study demonstrates a small but statistically significant association with improved survival for HER2-low tumors compared to HER2-negative tumors in MBC. Randomized data are necessary to further validate this discrepancy and determine if different management is warranted for each subtype.
Dynamic circulating tumor DNA (ctDNA) in monitoring trastuzumab deruxtecan (TDXd) activity for patients (pts) with advanced breast cancer: Preliminary results of a feasibility study.
Authors: Giordani Elena , Palazzo Antonella , Minucci Angelo , Pavese Francesco , Paris Ida , De Paolis Elisa , Ricciardi Elena , Orlandi Armando , Pannunzio Sergio , Tiberi Giordana , Carbognin Luisa , Bria Emilio , Giannarelli Diana , Scambia Giovanni , Giacomini Patrizio , Fabi Alessandra
Published: June 2022

1046

Background: Trastuzumab Deruxtecan (TDXd), a novel antibody-drug conjugate (ADC) that combines trastuzumab with a topoisomerase I inhibitor, has recently demonstrated high efficacy in HER2-overexpressing breast cancer after trastuzumab failure. Resistance to TDM1 have recently suggested to be dynamically associated with distinct circulating ctDNA species ( Allegretti et al, Mol Cancer 2021). A prospective study aiming to evaluate the feasibility of Liquid Biobsy (LB) in monitoring ctDNA in pts receiving TDXd in the national Expanded Access Program was conducted. Methods: In this prospective study, LB for ctDNA analysis (evaluating ‘ per pt’ ctDNA species and Variant Allelic Frequencies, VAF) was performed using 52-gene targeted NGS panel, in patients who progressed after two or more prior anti-HER2-based regimens and candidates to TDXd (3-weekly 5.4 mg/kg). This preliminary analysis reports data referring to Time-0 (T0) and T6 (cycle 6) assays. Results: From April 2021, LBs were collected for 14 pts and to date 8 are evaluable for LB. Median pts’ age was 59 yrs (range 38-72) and median number of previous anti-HER2 lines was 6 (2-11); 4 pts had Pertuzumab/Trastuzumab plus taxane as first-line and all pts received TDM-1. Median cycles of TDXd administered was 7.5 (1-10). At T0, 5/8 pts had at least one detectable ctDNA specie, and the remaining 3 developed at least one ctDNA at T6. ctDNA species and VAFs ranged from 1 to 5, and A0.1% to 68.94%, respectively. Decreases and increases were observed simultaneously in the same pt. The former varied from marginal to drastic, whereas the latter were invariably below 0.5% in VAFs. ctDNA monitoring was possible in 8/8 pts and at T6 ctDNA progression was detectable in 5/8 pts. Two pts displayed multiple HER2 copy number variations. Conclusions: The early results of this study suggest that considerable ctDNA burden, marked clonal complexity, and variable clonal response to TDXd can be found in pretreated HER2 positive patients, who progressed after antiHER2 therapies. Although the very small sample, this complex tumor evolution is surprising in light of the bystander payload effect of TDXd.
Clinical validation of a deep-learning–based model to predict lung cancer risk from chest X-rays.
Authors: Walia Anika , Raghu Vineet , Zinzuwadia Aniket , Lennes Inga Tolin , Lu Michael T
Published: June 2022

10507

Background: Screening with chest CT prevents lung cancer death, but only 5% of eligible Americans are screened. The updated 2022 Centers for Medicare and Medicaid Services (CMS) criteria expand eligibility to 50-77 year-olds, current or former (<15 years) smokers, with a ≥20 pack-year history. However, smoking quit date and pack-years are often not available in the electronic medical record (EMR), stymying identification of high-risk smokers for lung cancer screening (LCS). We previously developed a free, open-source deep-learning model (CXR-LC) that identifies smokers at high risk of lung cancer better than the 2015 CMS criteria, based on a chest X-ray (CXR) image automatically extracted from the EMR. CXR-LC was developed in the PLCO trial, an asymptomatic LCS population. The present study externally validates CXR-LC using existing CXRs obtained through usual care and compares CXR-LC to the expanded 2022 CMS lung screening eligibility criteria. Methods: Current or former smokers who had a routine clinical CXR in 2013-2014 were included. Patients with known lung cancer or who were undergoing LCS were excluded. Smoking status and 2022 CMS LCS eligibility were determined by manual review of the EMR. The primary outcome was 6-year incident lung cancer, identified using International Classification of Disease (ICD) codes and confirmed through discharge summaries and pathology reports. The CXR-LC model and the 2022 CMS eligibility criteria were compared for prediction of 6-year incident lung cancer. Results: Among 10,784 patients (mean age 63.1± 6.8 years; 61.0% male), CMS eligibility could be determined in 45% (4,886/10,784), with 55% missing pack-year or quit date data. In this population, 3.9% (191/4,886) developed lung cancer. The 2022 CMS criteria missed 57% (109/191) of lung cancers, while CXR-LC missed 8.9% (17/191, p < 0.001). After adjusting for sex, race, and prevalent COPD, the hazard ratio for CXR-LC eligibility (3.6, 95% CI [2.2,6.0]) was greater than for CMS eligibility (2.7, 95% CI [2.0,3.7]). In the 5,897 patients for whom CMS eligibility could not be determined, CXR-LC eligible patients had a 3-fold higher rate of lung cancer than CXR-LC ineligible patients (3.8% vs. 1.3%, p < 0.001). All CXR-LC eligible groups had 6-year lung cancer incidence >3.5%, above accepted screening risk thresholds of >1.5% and >2%. Conclusions: Using routine CXRs from the EMR, CXR-LC identified high-risk smokers who may benefit from LCS with CT, complementary to the 2022 CMS eligibility criteria. [Table: see text]