bluuebunny/crossref_metadata_2025 huggingface dataset:
Framework for developing cost-effectiveness analysis threshold: the case of Egypt
Authors: Fasseeh Ahmad N. , Korra Nada , Elezbawy Baher , Sedrak Amal S. , Gamal Mary , Eldessouki Randa , Eldebeiky Mariam , George Mohsen , Seyam Ahmed , Abourawash Asmaa , Khalifa Ahmed Y. , Shaheen Mayada , Abaza Sherif , Kaló Zoltán
Published: June 2024

Background

Cost-effectiveness analyses rarely offer useful insights to policy decisions unless their results are compared against a benchmark threshold. The cost-effectiveness threshold (CET) represents the maximum acceptable monetary value for achieving a unit of health gain. This study aimed to identify CET values on a global scale, provide an overview of using multiple CETs, and propose a country-specific CET framework specifically tailored for Egypt. The proposed framework aims to consider the globally identified CETs, analyze global trends, and consider the local structure of Egypt’s healthcare system.

Methods

We conducted a literature review to identify CET values, with a particular focus on understanding the basis of differentiation when multiple thresholds are present. CETs of different countries were reviewed from secondary sources. Additionally, we assembled an expert panel to develop a national CET framework in Egypt and propose an initial design. This was followed by a multistakeholder workshop, bringing together representatives of different governmental bodies to vote on the threshold value and finalize the recommended framework.

Results

The average CET, expressed as a percentage of the gross domestic product (GDP) per capita across all countries, was 135%, with a range of 21 to 300%. Interestingly, while the absolute value of CET increased with a country’s income level, the average CET/GDP per capita showed an inverse relationship. Some countries applied multiple thresholds based on disease severity or rarity. In the case of Egypt, the consensus workshop recommended a threshold ranging from one to three times the GDP per capita, taking into account the incremental relative quality-adjusted life years (QALY) gain. For orphan medicines, a CET multiplier between 1.5 and 3.0, based on the disease rarity, was recommended. A two-times multiplier was proposed for the private reimbursement threshold compared to the public threshold.

Conclusion

The CET values in most countries appear to be closely related to the GDP per capita. Higher-income countries tend to use a lower threshold as a percentage of their GDP per capita, contrasted with lower-income countries. In Egypt, experts opted for a multiple CET framework to assess the value of health technologies in terms of reimbursement and pricing.
Stem anteversion is not affected by proximal femur geometry in robotic-assisted total hip arthroplasty
Authors: Marcovigi Andrea , Grandi Gianluca , Bianchi Luca , Zambianchi Francesco , Pavesi Marco , Catani Fabio
Published: June 2024

Background

In the present study, the surgeon aimed to align the stem at 5° to 25° in anteversion. The robotic technology was used to measure stem anteversion with respect to proximal femur anteversion at different levels down the femur.

Methods

A total of 102 consecutive patients underwent robotic-arm-assisted total hip arthroplasty (RTHA). 3D CT-based preoperative planning was performed to determine femoral neck version (FNV), posterior cortex anteversion (PCA), anterior cortex anteversion (ACA), and femoral metaphyseal axis anteversion (MAA) at 3 different levels: D (10 mm above lesser trochanter), E (the midpoint of the planned neck resection line) and F (head-neck junction). The robotic system was used to define and measure stem anteversion during surgery.

Results

Mean FNV was 6.6° (SD: 8.8°) and the mean MAA was consistently significantly higher than FNV, growing progressively from proximal to distal. Mean SV was 16.4° (SD: 4.7°). There was no statistically significant difference (P = 0.16) between SV and MAA at the most distal measured level. In 96.1% cases, the stem was positioned inside the 5°–25° anteversion range.

Conclusions

Femoral anteversion progressively increased from neck to proximal metaphysis. Aligning the stem close to femoral anteversion 10 mm above the lesser trochanter often led to the desired component anteversion.
Multivariate statistical regression analysis and relative quantification based on dimensional-reduction method to compare the taste-active components of different chicken breeds
Authors: Xu Na , Wang Hao , Liu Lei , Xu Xinglian , Wang Peng
Published: June 2024

To compare the difference of non-volatile taste-active flavor components of different chicken breeds, four Chinese native yellow feather broilers including Langshan chicken, Chongren chicken, Luyuan chicken and Wenchang chicken were used in the experiment. The contents of free amino acids, 5'-nucleotides and minerals were determined by standard method, and then five principal components were extracted from the multi-index system based on the principal component analysis (PCA). Combined with the Mahalanobis distance analysis method and sensory evaluation results, the advantages and characteristics of each chicken breed were evaluated. The results showed that different kinds of chicken had their own advantages in different evaluation dimensions. The Equivalent umami concentration (ECU) of Wenchang chicken, which had the highest content of amino acids, was 12 g monosodium glutamate (MSG)/100 g, indicating the umami taste of it was very intense. The indexes of Langshan chicken were relatively uniform, with slightly higher mineral content, its overall Mahalanobis distance score was more similar to the "best standard". According to the Mahalanobis distance score, although the difference in amino acid content among each species was the largest, the overall score was more affected by the content of minerals and nucleotides, and there was interaction between each nutrient, which had an impact on the overall Mahalanobis distance score. The sensory evaluation results indicated that Wenchang chicken was the most superior among the taste of the four varieties investigated. Finally, taste compounds affecting the difference of chicken varieties were analyzed by partial least squares regression (PLS), resulting in order of mineral (Ca2+, Mg2+, PO43−) > nucleotide (AMP, IMP) > amino acid. This could provide a theoretical basis for quantitative oriented flavor processing and consumer choice of chicken.

Graphical Abstract
Depressive symptoms and coping patterns in a sample of Egyptian mothers of ADHD children
Authors: Serag Rehab , Hamed Marwa Abdel Meguid , Mahmoud Dalia Abdel Moneim , Elabd Esraa Fakhry Mahmoud , Kasem Rania Elsayed
Published: June 2024

Background

Attention-deficit/hyperactivity disorder (ADHD) is considered to be one of the most common neurodevelopmental conditions found in children. The global prevalence in the age group 6–17 years falls between 2 and 18%. Studies have found that mothers of ADHD children are more prone to experience depression, anxiety, social isolation, stress, and self-blame.

Aims and objectives

To assess the prevalence of depression and its severity among mothers with children found to have ADHD compared to mothers of the control group, we also investigate the coping mechanisms employed by mothers with ADHD children and identify any potential correlation between coping strategies utilized by mothers in the case group and the severity of depression.

Patients and methods

In this cross-sectional study, we recruited 100 participants from the outpatient child psychiatry clinic at Ma’amoura Psychiatric Hospital in Alexandria, Egypt. Two participant groups were assembled: Group I (case) consisted of 50 mothers whose children had ADHD, and Group II (control) consisted of 50 mothers whose children did not have ADHD. Both groups underwent the General Health Questionnaire (GHQ-28), Beck Depression Inventory (BDI-II), and Coping Orientation to Problems Experienced (COPE) inventory.

Results

A significant relationship was observed between the Beck Score and hyperactive and combined ADHD types; however, no significant correlation was found between the Beck Score and the inattentive ADHD type. Regarding the coping styles with stress, the current study’s results found that in (case group) turning to religion had the highest sub-scale mean, followed by seeking social support and emotional support, while the lowest sub-scale score mean was humor, followed by denial. By employing univariate logistic regression analysis to identify depression predictors in group I, the results showed that the increase in the score of less useful coping by 1 was a probable factor to increase the possibility of depression by OR = 1.438 (1.186–1.743). Combined and hyperactive ADHD types were found to increase the risk of depression by OR 6.706 (1.309–34.353).

Conclusion

Depressive complaints were more prevalent among mothers of children with ADHD compared to the control group. We found a statistically important relationship between Beck Depression Scores (depressive symptom severity) in mothers with ADHD children and having hyperactive or combined ADHD types in their children. We also found a statistically significant positive correlation between the severity of depression and some coping styles as turning to religion and seeking social support.
A case of intermittent bilious emesis in a term neonate: a case report and brief review of literature
Authors: Mudugere Asha , Pradhan Antaryami , Kumar Vijay , Nanda Debasish
Published: June 2024

Background

Neonatal intestinal obstruction is a complex condition that poses challenge in management. Prompt recognition and appropriate management are crucial to prevent complications. We present a case of a term neonate with intermittent bilious vomiting.

Case presentation

The baby underwent routinely performed investigations, including abdominal radiography and ultrasound, which provided inconclusive results. However, contrast-enhanced computed tomography revealed a web at duodenojejunal flexure. Exploratory laparotomy confirmed the diagnosis, and surgical intervention was performed. The baby’s postoperative course was prolonged with a gradual transition from parenteral nutrition to enteral feeds.

Conclusion

This case highlights a rare cause of intestinal obstruction, the unusual location of duodenal web, the importance of maintaining a high index of suspicion for intestinal obstruction, even in the absence of classical signs, and the value of utilizing contrast-enhanced computed tomography when initial investigations are inconclusive.
A phase 1 study of liposomal irinotecan in patients with advanced breast cancer.
Authors: Fan Ying , Zhang Qingyuan , Yan Min , Qu Xiujuan , Yin Yongmei , Sun Tao , Yang Jin , Wang Ying , Wang Xu , Niu Zhaofeng , Wang Xinshuai , Sun Sanyuan , Zhao Weihong , Liu Yanping , Miao Niu , Xuemin Zhao , Xu Binghe
Published: June 2024

1080

Background: Liposomal irinotecan (HE072) is a liposomal formulation that encapsulates irinotecan in a lipid bilayer vesicle, and as a generic drug, had been approved in China, recently, in patients with pancreatic cancer after gemcitabine treatment. Advanced triple negative breast cancer (TNBC) has very poor prognosis and limited treatment choices. Here we present results of breast cancer treated with HE072 in patients with highly pre-treated metastatic TNBC and HER2 negative breast cancer brain metastasis (BCBM). Methods: HE072-CSP-002 was a phase 1 study, consisting of two parts, dose escalation and expansion part (part 1) and expansion cohort part (part 2). In part 1, standard 3+3 design was used to investigate up to three dose levels of HE072 (50 mg/m2, 70 mg/m2 and 90 mg/m2), up to 6-9 additional subjects may be enrolled for dose expansion. In part 2, patients were enrolled in two cohorts (TNBC cohort and BCBM cohort), and received HE072 70 mg/m2 every two weeks (Q2W). The primary endpoints were the maximum tolerated dose (MTD) and recommended phase 2 dose (RP2D), and the incidence and severity of treatment emergent adverse events (TEAEs). Secondary endpoints included progression free survival (PFS), objective response rate (ORR), overall survival (OS). Results: As of June 5th, 2023, 119 patients were enrolled, including 101 patients with TNBC and 18 patients with HER2 negative BCBM (part 1: n=27; part 2: n=92). In the part 1, one dose-limiting toxicity (grade 3 nausea and grade 3 vomiting) was observed at 70 mg/m2 dose level, and MTD was not reached. A total of 115 patients (96.6%) had at least one TEAEs of any grade, and 55 patients (46.2%) had ≥grade 3 TEAEs. The most common ≥grade 3 TEAEs related to HE072 included neutropenia (21.0%), leukopenia (18.5%), diarrhea (10.1%), anemia (9.2%) and hypokalemia (8.4%). Eighty-three (82.2%) of the 101 patients with TNBC were evaluable for response. After a median follow-up of 10.1 months (range 8.8-10.8), 22 patients (26.5%, 95%CI 17.4-37.3) achieved overall response, which were all partial response and 58 patients (69.9%, 95%CI 58.8-79.5) achieved disease control. The median PFS and OS were 4.8 months (95%CI 3.9-5.8) and 14.1 months (95%CI 11.2-not reached), respectively. 12(66.7%) of the 18 patients with HER2 negative BCBM were evaluable for response. 1 patient (8.3%, 95%CI 0.2, 38.5) achieved overall response, which is partial response and 8 patients (66.7%, 95%CI 34.9, 90.1) achieved disease control. The median PFS was 5.6 months (95%CI 1.4~ not reached), 12-month OS rate was 55.5%. Conclusions: HE072 exhibited excellent antitumor activity in heavily pre-treated patients with TNBC and HER2 negative BCBM with acceptable safety profiles. 70 mg/m2 Q2W was determined as the RP2D. Further clinical trials are under plan. Clinical trial information: NCT04728035 .
Trilaciclib combined with sacituzumab govitecan (SG) in metastatic triple-negative breast cancer (mTNBC): Updated phase 2 safety and efficacy results.
Authors: Seneviratne Lasika C. , Harnden Kathleen Kiernan , Blau Sibel , Danso Michael A. , Berz David , Guaqueta Delia Constanza , Schwerkoske John F. , O'Shaughnessy Joyce , Patt Debra A. , Bardia Aditya , McCann Kelly Elizabeth , Beelen Andrew Paul , Zhang Jingshan , Yi John S. , Hurvitz Sara A. , Mardones Mabel Alejandra
Published: June 2024

1091

Background: Trilaciclib, a reversible cyclin-dependent kinase 4/6 inhibitor, protects hematopoietic stem and progenitor cells during chemotherapy (myeloprotection). In a phase 2 trial in mTNBC (NCT02978716), administering trilaciclib prior to chemotherapy enhanced T-cell activity and modulated antitumor immunity. In a phase 3 trial (ASCENT; NCT02574455), the antibody–drug conjugate SG significantly extended overall survival (OS) versus single-agent chemotherapy (12.1 vs 6.7 months) but was associated with increased neutropenia (any grade, 63% vs 43%; grade 3/4, 51% vs 33%) and diarrhea (any grade, 59% vs 12%; grade 3/4, 10% vs < 1%). This phase 2 single-arm trial was designed to assess safety and efficacy of trilaciclib prior to SG in mTNBC (NCT05113966). Methods: Eligible patients (≥ 2 prior systemic therapies [≥ 1 in the metastatic setting]; measurable disease; confirmed hormone receptor- and human epidermal growth factor receptor 2-negative status; Eastern Cooperative Oncology Group performance status 0 or 1) received intravenous trilaciclib 240 mg/m2 prior to SG 10 mg/kg on days 1 and 8 of each 21-day cycle until disease progression or toxicity. Tumor assessments occurred at screening, every 6 weeks through week 26, then every 9 weeks until disease progression or subsequent anticancer therapy. Endpoints included antitumor efficacy, myeloprotection, and safety and tolerability. Results: As of January 2, 2024, 30 female patients had been enrolled (median age, 56 years) and completed a median 6 (range, 2–29) cycles. Median follow-up was 11.2 months. Safety is summarized in the Table. The confirmed overall response rate (95% CI) was 23.3% (9.9–42.3), the clinical benefit rate was 46.7% (28.3–65.7), and the median duration of response was 9.1 (4.0–not estimable) months. Median progression-free survival was 4.1 (2.2–7.3) months. OS data are not yet mature; currently, median OS among patients receiving trilaciclib prior to SG is 17.9 (9.9–not estimable) months. Conclusions: Adding trilaciclib prior to SG reduces the rate and severity of multiple adverse events, notably neutropenia and diarrhea, compared with results from trials of SG alone. Preliminary data suggest clinically meaningful OS outcomes among patients receiving trilaciclib prior to SG compared with historical data for SG alone; however, caution should be exercised when interpreting results from cross-trial comparisons. Mature OS data will be presented. Clinical trial information: NCT05113966 . [Table: see text]
Interventions of the nurse navigator in the identification and management of toxicities after the start of treatment in patients with cancer using antineoplastic therapy.
Authors: Messias Anna Carolina R , Bergerot Cristiane Decat , Faria Andre , Gregoli Camila Tolomelli , Vidal Alice Sousa , Carneiro Juliana Torres , Ferrari Bruno Lemos
Published: June 2024

12139

Background: Monitoring symptoms during chemotherapy is crucial as patients experience adverse effects, requiring therapeutic modifications, supportive care, and education. Patient navigation provides individualized assistance, overcoming barriers to healthcare access for patients, families, and caregivers. A previous study (Tabriz et al. JAMA Netw Open 2023) has shown that 52% of emergency room (ER) visits can be preventable. Thus, this study sought to determine effect of a nurse navigation program on reducing the rate of ER visit. Methods: This retrospective study was conducted from June to December 2023 in two cancer centers within the Oncoclinicas Network, located in the Southeast and Northwest regions of Brazil. Eligible patients were diagnosed with breast, lung, and gastrointestinal cancer, and were undergoing treatment with chemotherapy and/or immunotherapy. These patients were monitored by nurse navigators at post-therapy. Interventions were categorized as home management (care provided at patient’s home), outpatient (referral to the treatment clinic), and hospital (referral to emergency care). All toxicities were graded according to the Common Terminology Criteria for Adverse Events 5.0. Results: A total of 531 patients were included in the analysis, with the majority aged over 61 years old (44.4%), diagnosed breast (%) or colon (%) cancers. Throughout the six month study period, 3,201 toxicities were identified, with the majority graded between 1 and 2 (95.9%). This resulted in 91.9% of patients being managed at home or referred to the outpatient care. The cumulative proportion of patients having their symptoms managed at home or outpatient care is significantly higher than historical controls (P=0.001). Conclusions: Our findings highlight the effectiveness of a nurse navigation program in managing toxicities and symptoms, preventing ER visit. These findings underscore the importance of this program in optimizing patient care and reducing the burden on healthcare facilities. Further research and implementation of such programs may contribute to improved outcomes and patient satisfaction in oncological care.
Cancer clinical trial participation in socioeconomically vulnerable patients: A risk model to aid in targeted interventions.
Authors: Szarama Katherine , Unger Joseph M.
Published: June 2024

1529

Background: In patients with cancer, those with lower income are 30% less likely to participate in clinical trials. Lower income individuals face direct and indirect costs that can make participation in a clinical trial prohibitive. However, a broader evaluation of specific behavioral, information, insurance, and area-level variables that could contribute to this disparity has not been conducted. We aimed to develop and validate a model to identify socioeconomically vulnerable patients at high risk of non-participation in clinical trials. Methods: We used data from the Health Information National Trends Survey (HINTS), a national cross-sectional survey about knowledge of, attitudes toward, and use of health-related information. We analyzed HINTS survey databases that included questions about whether patients with cancer participated in a clinical trial (survey years 2014, 2017, and 2020). We examined 21 different demographic, socioeconomic, behavioral, geographic, and health information questions. We derived a risk model to predict clinical trial participation in a random set of 60% of participants using best subset selection with k-fold cross validation. The derived model was validated in the remaining 40% of participants. Logistic regression was used. Results: We examined N=1,023 participants with household income <$75,000, the current median in the U.S. In the training dataset of n=614 participants, a model with 5 variables was identified. Non-Hispanic White patients and patients without a college education, with high levels of distrust, with high levels of anxiety or depression, and from non-urban areas were all at lower risk of trial participation. We summed the adverse risk factors for all individuals; a risk score with 4 levels was constructed based on distribution quartiles. In the independent validation cohort (n=409), each increase in level of adverse risk factors was associated with a 42% reduction in the odds of trial participation (OR=0.58, 95%-CI, 0.40-0.84, p=.004), indicating successful model validation. Among all individuals, trial participation rates decreased from 18.6% to 7.5% to 4.6% to 2.8%, respectively, as the number of adverse risk factors increased (in quartiles) from 0-1 to 2 to 3 to 4-5. Individuals with 4 or 5 risk factors (vs. those with 0-1 factors) were 87% less likely to participate (OR=0.13, 95% CI, 0.05-0.31, p<.0001). Conclusions: We developed and validated a 5-variable risk model that identified a large set of lower income individuals at lower risk of trial participation. In a first-time observation, psychosocial variables were shown to be meaningful predictors of lower trial participation. These findings could aide in the early identification of patients who may benefit from additional support to navigate the treatment trial decision making process, in the name of more equitable participation in trials for all patients.
Continuous remote monitoring of performance status in patients with NSCLC through fitness tracker–derived life-log data.
Authors: Bang Yeong Hak , Lee Suyeon , Kim Taehee , Suh Hongyiel , Kim Mansu , Park Sehhoon
Published: June 2024

1568

Background: Traditional methods for assessing the performance status of cancer patients often rely on clinical evaluations and patient-reported histories. This study utilizes life-log data derived from fitness trackers (FTs) in patients with non-small cell lung cancer (NSCLC) to offer a comprehensive and dynamic perspective on performance status throughout their treatment. Methods: Patients with NSCLC scheduled for a minimum of 12 weeks of treatment were enrolled. Custom software facilitated the remote collection of life-log data from participants' FTs (Fitbit Inspire 3), encompassing step count, calories burned, heart rate, sleep patterns, etc. Quality of life surveys assessing patient-reported outcomes (PROs) were completed during regular visits (every 3 weeks) and unscheduled visits (USV), in addition to collecting clinical data such as laboratory parameters and body composition metrics. An end-of-monitoring survey assessed participants' familiarity with this monitoring approach. The study aimed to correlate FT data with clinical parameters and identify patterns predictive of treatment related USVs. Results: Of the 98 enrolled patients, 69 patients (70.4%) completed the 12-week follow-up. The cohort predominantly consisted of older adults (≥65 years) (55.1%) and patients in palliative care (75.5%), with most undergoing cytotoxic chemotherapy (66.3%) and some receiving oral agents (20%). FT-based remote monitoring revealed that older patients had a comparable 12-week completion rate to younger patients. (69.2% vs. 76.2%, P=0.604). Analysis of life-log data from three days before a visit (D-3) to the visit day (D0) showed significant reductions in average step counts ( P=0.022) and walking distance ( P=0.021) for USVs compared to regular visits, while resting heart rate (HR) showed a significant increase for USVs ( P=0.049). PRO-based PROMIS physical function scores and EQ-5D-3L scores showed a significant correlation with both D-3 to D0 acquired resting HR ( P<0.001, P=0.002) and average step counts ( P=0.011, P=0.013), respectively. End of monitoring survey was done from 72 participants indicating high satisfaction and familiarity with the FT-based remote monitoring system, median score of 90 out of 100. Conclusions: FT-derived life-log data effectively captured dynamic performance status in NSCLC patients, correlating with clinical outcomes and PRO. These findings support further research into FT data's predictive value for clinical interventions, underscoring its potential in personalized remote patient management.
Digital health program for patients with cancer to support self-management: A retrospective real-world analysis.
Authors: Bjarnadottir Olof K. , Dobies Bartosz , Ísberg Ari Páll , White Alice Jean , Jónasdóttir Sigríður Svala , Oddsson Saemundur
Published: June 2024

1570

Background: Sidekick Health’s 13-week digital health program was built to support cancer self-management. It was available free of charge to US-based cancer patients through commercial health insurance. The program includes disease education, mindfulness, medication adherence support, and asynchronous messaging with a care manager. We hypothesized that highly engaged users had reduced symptom frequency and severity, and improved quality of life (QoL) outcomes. Methods: In-app data were analyzed for registrations Aug 2021-Jan 2024: n(registered)=1286; n(retained ≥7 days)=795; n(QoL/symptoms)=284. QoL was defined as self-reported sleep quality, energy and stress (10-point scale, ≤4x/week). Symptoms were also self-reported (10-point scale, ≤7x/week). Generalized linear mixed models for repeated measures were used to investigate QoL, symptom frequency and severity changes over the program. Subgroup analysis: weekly iterative k-means clustering into highly- and less-engaged (based on total active days) to mitigate survival bias. Results: Diverse patients from 37 states engaged: mean age 58.0 years (SD=10.5), 71% female; 49% diagnosed <6 months ago, 36% ≥12 months ago; 23% early-stage disease, 26% stable disease, 6% in remission and 2% terminal; 60% received chemotherapy, 24% radiation therapy, and 21% immunotherapy. Most (61%) registered users were active after 7 days and 29% after 90 days. Less-engaged users reported higher mean baseline weight (85.3kg (SD=26.7)) vs highly engaged (76.9kg (SD=18.3); p=0.010) but were otherwise similar (age, gender, height, time since diagnosis and treatment: p>0.05). For QoL, highly engaged users had improved energy (p=0.013) and sleep (p=0.002), but not stress (p=0.164) vs less engaged. A significant time-group interaction for sleep (p<0.001) showed highly engaged users had better sleep, and larger improvements over time vs less-engaged. Overall, users reported fewer symptoms over the program (IRR (95% CI)=0.965 (0.953, 0.978), p<0.001). Symptom frequency decreased significantly for stress (p=0.034) and nausea (p=0.003), but not numbness (p=0.320) or fatigue (p=0.530). Highly engaged users’ symptom severity had a downward trajectory, compared with less-engaged, for fatigue (p=0.044) and nausea (p=0.001), but not stress (p=0.234) or numbness (p=0.680). Conclusions: Theprogram was accessed by a broad patient group and retention was high. Highly engaged users reported improved QoL (energy, sleep) and reduced symptom severity (fatigue, nausea). Total symptom frequency was reduced over the program, as well as for stress and nausea specifically. These findings indicate digital self-management is not only achievable for patients with cancer, but that higher engagement may improve patient-reported outcomes.
Preliminary exploration of Trop2 ADC in combination with immune checkpoint inhibitors in the different molecular subtypes of invasive breast carcinoma.
Authors: Liu Yueping , Jiang Hanxu , Deng Huiyan , Li Jinze , He Jiankun , Liu Xudi
Published: June 2024

e12558

Background: Human trophoblastic cell surface antigen 2 (Trop2) is a transmembrane protein overexpressed in breast cancer tissues. However, it is present at minimal levels in adult somatic tissues, making it an ideal target for treatment with antibody-drug conjugates (ADCs). Sacituzumab govitecan, an anti-Trop2 ADC, has been approved for the treatment of triple-negative breast cancer and urothelial cancer. Recent studies have demonstrated that human cytotoxic T lymphocytes can recognize Trop2. Accordingly, we aimed to assess the role of Trop2 in the tumor immune activity of different subtypes of breast cancer, and laying the foundation for further studies on the efficacy of the combination of Trop2 ADC and immune checkpoint inhibitors in breast cancer. Methods: We retrospectively retrieved tissues from 152 invasive breast carcinoma of no special type and 111 benign breast tumor tissues and undergoing surgical resection at our institution from 2018 to 2023. Immunohistochemistry was used to detect Trop2 and PD-L1 expression and lymphatic invasion in patients, and their correlations with clinicopathological factors were analyzed. Trop2 expression was evaluated using the H-score. The median as the cut-off value, a score of 0–240 indicated low expression, and 240–300 indicated high expression. Cases with CPS ≥ 1% were considered positive for PD-L1. Results: The expression was Trop2 in breast cancer tissues than in benign tumor tissues (P<0.0001). Immune infiltration analysis suggested that Trop2 expression was correlated with immune cell infiltration and the abundance (P<0.001). Kaplan–Meier plotter analysis demonstrated that high Trop2 expression was related to poor prognosis in patients with triple-negative breast cancer (overall survival: HR=1.53, P=0.029; relapse-free survival: HR=1.26, P=0.045). In contrast, Trop2 expression was not significantly associated with prognosis in other breast cancer subtypes. However, there was no statistically significant correlation found between PD-L1 expression and Trop-2 expression in breast cancer. Conclusions: The findings suggest that Trop2 correlates with poor prognosis and immune cell infiltration in breast cancer. This indicates the role of Trop2 as a potential prognostic biomarker, laying the foundation for further research focusing on the immune regulatory role of Trop2. [Table: see text]
Trastuzumab, pertuzumab and nab-paclitaxel plus pyrotinib or not in neoadjuvant treatment of HER2-positive breast cancer: A multi-center, randomized, open-label, phase II study.
Authors: Chen Xiaosong , Huang Jiahui , Tong Yiwei , Ren Weili , Yu Jing , Gao Weiqi , Zhu Siji , Hong Jin , Wu Jiayi , Huang Ou , He Jianrong , Chen Weiguo , Li Yafen , Shen Kunwei
Published: June 2024

e12634

Background: Trastuzumab plus pertuzumab (TP) combined with chemotherapy is the standard neoadjuvant treatment regimen for HER2+ breast cancer. Anti-HER2 tyrosine kinase inhibitor, pyrotinib, shows great efficacy in HER2+ metastatic breast cancer, but lacking efficacy data on the basis of TP and chemotherapy in the neoadjuvant setting. This study aims to evaluate the efficacy and safety of TP plus nab-paclitaxel with or without pyrotinib as neoadjuvant treatment in HER2+ breast cancer. Methods: Stage II-III HER2+ breast cancer patients, stratified by disease stage (II vs. III) and hormone receptor (HR) status (positive vs. negative), were randomized 1:1 into the pyrotinib group or the control group. Both groups received a combination of 3-weekly TP and weekly nab-paclitaxel for 12 weeks. The pyrotinib group was concurrent given 320mg pyrotinib once daily. Primary endpoint was the total pathological complete remission (tpCR), defined as no invasive cancer in the breast and axillary lymph node. Results: From Nov 2020 to Apr 2023, a total of 109 patients were enrolled, with 108 receiving treatment: 55 in the pyrotinib group and 53 in the control group.The tpCR rate was 65.5% (95% CI: 51.4%, 77.8%) in the pyrotinib group, which shows no significant difference with the control group [60.4% (95% CI: 46.0%,73.5), P = 0.585). The breast pathological complete response (bpCR) rates were 70.9% (95% CI: 57.1%,82.4%) and 64.2%(95% CI: 49.8%,76.9%) in the pyrotinib and control group, respectively (P = 0.453). In the pyrotinib group, 52 (94.5%), 31 (56.4%), and 23 (41.8%) patients experienced dose-interruption, dose-reduction, and discontinuation of pyrotinib, respectively. The most common grade ≥3 adverse events in the pyrotinib and control groups were diarrhea (58.1% vs. 0%), decreased neutrophil count (23.6% vs. 15.1%), and decreased white blood cell count (16.4% vs. 7.5%). Conclusions: Our study showed pyrotinib didn’t significantly improve tpCR rate with pyrotinib on the basis of TP and nab-paclitaxel neoadjuvant therapy of HER2+ breast cancer. Concurrent pyrotinib treatment with TP was associated with a high rate of severe diarrhea. Further biomarker analyses are needed to identify which population would receive great benefit with neoadjuvant pyrotinib therapy in HER2+ breast cancer. Clinical trial information: NCT04398914 .
Intracellular retention of TCRαβ/CD3 to generate novel allogeneic CAR-T cells targeting CLL1 for treating acute myelocytic leukemia.
Authors: Li Jun , Liu Kaichun , Xu Guanggui , Chen Shanshan , Zhang Yinhang
Published: June 2024

e14532

Background: The prognosis of patients with R/R AML is poor and treatment remains challenging. Human C-type lectin-like molecule 1(CLL1) is a type II transmembrane glycoprotein that is highly expressed on AML but is absent on normal HSCs. Clinical studies have shown that autologous CLL-1 is a novel and promising target for the treatment of AML. But autologous CAR-T therapy has been complicated by long production time, high-cost and risks of manufacturing failure, and allogeneic CAR-T cells can overcome these hurdles. Methods: A novel non-gene-editing allogeneic CAR-T platform was developed on the base of intracellular retention of membrane proteins, and named ThisCART (This = TCR and/or HLA-I intracellular sequestered). CLL1-directed ThisCART cells are readily produced with a single lentiviral vector, encoding both a CLL1-targeting CAR and an anti-CD3 single chain antibody with the KDEL peptide fused to its C-termini. The surface expression of CAR and TCRαβ/CD3 was measured by flow cytometer. Specific tumor cytotoxicity was evaluated both in vitro and in vivo. Furthermore, the safety of donor derived ThisCART cells were tested in a xenogeneic GvHD model. Results: The manufacturing platform of CLL1 ThisCART was able to achieve over 150-folds of ex vivo CAR-T expansion in all batches, with the purity of products (CAR-positive/TCRαβ-negative) above 99%. In preclinical models, CLL1 ThisCART did not induce GvHD, and exhibited superior antitumor function compared to benchmark (WO2017091615A) and conventional CLL1 CAR-T cells. CLL1 ThisCART cells were readily produced to a quantity and quality supporting clinical investigation. Conclusions: CLL1 ThisCART cells based on intracellular retention of TCRαβ/CD3 complex demonstrated superior CLL1-dependent cytotoxicity and no xenogeneic GvHD in murine models. With streamlined single-vector-based production, enhanced CAR signaling and potent cytotoxicity and favored preclinical safety profile, CLL1 ThisCART warrant clinical investigation.
Pan-tumor circulating tumor DNA testing in the community oncology setting.
Authors: Raska Paola , Su Zhaohui , Robert Nicholas J
Published: June 2024

e14556

Background: Circulating tumor DNA (ctDNA) technology allows for monitoring the genomic profile of cancer over time non-invasively, and in a way that is more representative of existing tumor clones than tissue sampling. The clinical and research applications of this new technology are numerous, and they are potentiated through serial ctDNA testing of individual patients. It is important to identify and characterize real-world data sets that will permit the development of both ctDNA’s clinical and research applications. Methods: This is an observational study of breast, non-small cell lung cancer (NSCLC), colorectal and prostate cancer patients who had ctDNA testing in The US Oncology Network from August 2014 to August 2023. All unique ctDNA reports per patient were collected, along with the report dates and patient characteristics. Rate of change in number of unique reports per month through time was evaluated as well as frequencies of serial testing and median time lapse between diagnosis and date of first ctDNA test by cancer type. Results: Number of new unique ctDNA testing reports per month increased for The US Oncology Network from 2014 through 2018 at a rate of 0.86 (95% CI [0.70, 1.02]). From 2018 to 2023 this rate increased to 5.87 (95% CI [5.16, 6.59]) new reports per month. The total number of unique patients with one of the 4 cancer indications and at least one ctDNA test during the study time period was 10,852. The cancer indication with greatest number of patients with ctDNA testing is NSCLC with 5,503 patients, followed by breast with 2,408, and colorectal and prostate with 1,544 and 1,397 respectively. Black patients were equally represented across all 4 cancers at rates of 13.6% for colorectal, 12.7% for breast, and 12% for NSCLC and prostate. Patients over 65 made up 66% for prostate and NSCLC but only 38% and 32% for colorectal and breast respectively. Most patients presented with a single ctDNA test (n = 9482), but an important proportion presented with 2 serial ctDNA tests or more (n = 1370, 12.6%).The median time between either cancer diagnosis date or date of first visit in The Network and the date of the first ctDNA test report was 39 days for NSCLC, 1,690 days for breast, 377 days for colorectal and 772 days for prostate, and presented with a skewed, long right tailed distribution. Median times were similar for Black and White patients across all cancers. Conclusions: The number of patients with ctDNA testing data available is increasing through time without evidence of plateauing. Although the total number of patients represented is still a very small fraction of the total patient population, the rate of increase in number of new reports through time is equivalent to an exponential increase in the total number of reports. 12.6% of patients presented with two tests or more, potentially allowing for pre and post treatment assessments. There’s an opportunity to better align cancer research and cancer treatment paradigms with this new technology.
Novel engineered regulatory macrophages combined with ICIs for post-transplant recurrence after liver transplantation for HCC.
Authors: Hu Yongwei , Zhang Mingshen , He Kaiming , Lv Lei , Yu Haoyuan , Li Siqi , Liu Wei , Li Hua , Yi Shuhong , Yang Yang , Ye Linsen
Published: June 2024

e14582

Background: Liver transplantation is the most effective treatment for early-stage hepatocellular carcinoma (HCC), but post-transplant recurrence limits the efficacy of surgery and affects the patient prognosis. Most of the current attempts to apply immune checkpoint inhibitors (ICIs) to posttransplant recurrence have resulted in either acute allograft rejection or tumor progression, which may be related to the disruption of the immune balance that maintains immune tolerance and enhances immune activation. Methods: Therefore, we constructed an engineered regulatory macrophages (Mregs) with anti-tumor capacity in the transplant setting using reprogrammed liposomes to precisely regulate the immune microenvironment of post-transplant recurrence, in order to create suitable conditions for the safe use of ICIs. Results: Experimentally, Mregs were shown to prolonged allograft survival without promoting tumor development. Through fusing with the Mregs membrane, reprogrammed liposomes insert an anti-CD47 lipid shell onto the surface, enhancing phagocytosis against tumor. The drug-loaded inner core entered into the cytoplasm to reprogram Mregs. Tomivosertib downregulated the expression of PD-L1 and attenuated the immunosuppressive effect. Pexidartinib inhibited the polarization of the M2 pathway and upregulated the expression of CD80, CD86, and MHC II, enhancing the ability of antigen presentation. Combination with anti-PD-L1 antibodies can enhance anti-tumor effect without accelerating allograft rejection. Both in vivo and in vitro results demonstrate that engineered Mregs provide conditions for the safe use of anti-PD-L1 antibodies in the context of transplantation. Conclusions: Engineered Mregs combined with ICIs enhances immunotherapeutic efficacy and provides a viable therapeutic approach for posttransplant recurrence after liver transplantation for HCC.
PD-1 checkpoint inhibitors related immune-mediated hepatitis in colon cancer: A systematic review and meta-analysis.
Authors: Sanikommu Dhruvi Reddy , Nadeem Ahmed , Uttam Chandani Kanishka
Published: June 2024

e14615

Background: Immune checkpoint inhibitors have revolutionized the management of advanced colon cancers by targeting programmed death-1 (PD-1) proteins. Along with PD-1, other checkpoint inhibitors PDL-1 and CTL4 have been approved for the treatment of various type of cancers since a decade. However, many immune-related side effects have been associated with them. There is limited data in the literature on PD-1 related hepatotoxicity, mainly immune mediated hepatitis. This systematic review and meta-analysis aim to study the impact of PD-1 checkpoint inhibitors on immune-mediated hepatitis in the context of colon cancer, its incidence among different immunotherapies, risk factors associated with it and exploring treatment modalities. Methods: The study was conducted in accordance with PRISMA guidelines. Multiple databases such as PubMed, EMBASE, Scopus, Cochrane Library and Web of Science from past 10 years were searched up to November 2023. Studies from cohort studies, randomized control trials and case series that have reported on immune-mediated hepatitis in colon cancer patients treated with PD-1 inhibitors were included. Results: Overall pooled incidence of immune mediated hepatitis was between 1% -5% with an average of 4.1% (95% CI, 2.8-5.8) among patients with advanced colon cancer treated with PD-1 inhibitors. Among different inhibitors, incidence was lowest with Pembrolizumab, around 1.4%; and highest with Cemiplimab with 5.1%. This is crucial in optimizing treatment for advanced colon cancers. The meta-analysis also found risk factors of male gender, older age and pre-existing liver-conditions (Hepatitis B and C), contributing to the development of hepatitis. Subgroup analysis will be performed to explore potential differences in incidence rates based on patient characteristics, dosages of medications, duration of treatment and concomitant medications. Other objectives include determining the timeline and grades of toxicity. Conclusions: By incorporating data from other studies and understating safety profiles, the findings will highlight the need for close surveillance for toxicity monitoring. This would also provide insight for clinical providers to make informed decisions regarding treatment selection. Toxicities are noted to be under-reported; hence we urge clinicians to report such immune toxicities. Further research is needed to elucidate underlying mechanisms to develop strategies for mitigating adverse events.
Comparison of pembrolizumab plus chemotherapy versus concurrent or sequential radiochemotherapy in patients with driver mutation-lacking lung adenocarcinoma presenting with recurrent laryngeal nerve invasion leading to hoarseness.
Authors: Lu Zhuming , Xu Shengshan , Ye Min , Shen Tao , Zhang Xin , Rao Dongping , Chen Jiarong , Lin Zhichao , Chang Mingzhang , Xiong Guoping , Li Ronggang , Wang Zhihui
Published: June 2024

e14635

Background: For patients with advanced non-small cell lung cancer (NSCLC), particularly those with adenocarcinoma lacking a driver mutation, the encroachment upon the recurrent laryngeal nerve causing hoarseness presents a substantial challenge in treatment. Such patients, at TNM stage IIIB or higher, may undergo platinum-based doublet chemotherapy combined with concurrent or sequential radiotherapy. Despite these treatments, survival rates remain modest, and quality of life is significantly impaired by symptoms such as hoarseness, dysphagia, and coughing. Recently, pembrolizumab combined with chemotherapy has emerged as a frontline treatment for adenocarcinoma patients, showing promising outcomes in unresectable, advanced stages of the disease. However, its efficacy in patients experiencing hoarseness due to recurrent laryngeal nerve involvement has not been previously investigated. Methods: Between September 2018 and October 2022, Jiangmen Central Hospital admitted 71 patients with advanced adenocarcinoma and hoarseness, who lacked a driver mutation as confirmed by NGS testing. After excluding patients who did not complete the treatment plan, the remaining subjects were randomly divided into two groups. The treatment group, consisting of 21 patients, received pembrolizumab, pemetrexed, and platinum-based doublet chemotherapy. The control group, also comprising 21 patients, underwent concurrent or sequential radiotherapy alongside pemetrexed and platinum-based chemotherapy. Results: Among the treatment group, hoarseness was reversed in 13 out of 21 patients, with a return to normal vocal function. In the control group, 5 out of 21 patients experienced a reversal of hoarseness. The treatment group showed superior outcomes in reversing hoarseness caused by recurrent laryngeal nerve involvement (p=0.013). The objective response rate (ORR) in the treatment group was 28.57%, with a disease control rate (DCR) of 66.67%. In contrast, the control group had an ORR of 9.52% and a DCR of 28.57% (p<0.05). The Progression-Free Survival (PFS), as calculated by the Kaplan-Meier survival curve method, was 11.77 months (95% CI: 11.19-12.35) in the treatment group and 7.53 months (95% CI: 6.73-8.33) in the control group, indicating a significantly higher survival rate in the treatment group (p<0.05). Conclusions: In patients with advanced lung adenocarcinoma, pembrolizumab combined with chemotherapy appears to effectively reverse hoarseness caused by recurrent laryngeal nerve involvement, higher objective response rates, and increased PFS. This suggests the necessity for multicentric, prospective, evidence-based studies in the treatment of lung adenocarcinoma patients with hoarseness due to recurrent laryngeal nerve invasion.