bluuebunny/crossref_metadata_2025 huggingface dataset:
Perceived feasibility, acceptability and impact of the family involvement intervention for severe mental illness: a qualitative study in Masaka - Uganda
Authors: Turiho Andrew Kampikaho , Musisi Seggane , Alinaitwe Racheal , Okello Elialilia S. , Bird Victoria Jane , Priebe Stefan , Sewankambo Nelson
Published: June 2024

Background

The burden of severe mental illness is high in low-resource settings like Uganda. But most affected people are not treated due to inadequacy of sectoral funding and trained mental health professionals. Medication has hitherto been the main method of treatment for severe mental illness worldwide. However, there is a growing realization that the use of community-based resource-oriented interventions like the family involvement are more effective and suitable for under-resourced settings. But there is a paucity of information about its applicability in Uganda.

Methods

We based the intervention at the mental health unit of Masaka Regional Referral Hospital, involving 30 patients with SMI, 60 family members and friends, and 6 mental health clinicians. It was delivered through regular monthly meetings of 5 patients, 10 caretakers, and 2 clinicians each, for six months. A purposive sample of 15 patients, 15 caretakers, and 6 clinicians participated in this qualitative evaluation study after 6 months. Data was collected using in-depth interviews. Atlas.Ti (version 7.0.82) computer software was used in data analysis. Both priori and grounded codes were used to code data.

Results

We evaluated perceived feasibility, acceptability and impact of the intervention in the Ugandan context. The findings were largely positive. Feasibility was mainly driven by: the training of group facilitators, field support and supervision, prior relationship between participants, and scheduling and timing of meetings. Acceptability was supported by: anticipation of knowledge about mental illness, process and content of meetings, safety of meeting environment, and choice of participants and venue. Impact was majorly in domains of: knowledge about mental illness, psychosocial aspects of mental illness, networking and bonding, and patients’ quality of life. The success of the intervention would further be enhanced by its decentralization and homogenized composition of groups.

Conclusions

The intervention promises to spur improvement in the following main aspects of mental health services: accessibility since the meeting environment is more neutral and friendlier than the clinical setup; knowledge of mental illness; recognition of the important role of the family in management of mental illness; adoption of holistic approaches to mental illness; and quality of life of patients.
Minimization of occurrence of retained surgical items using machine learning and deep learning techniques: a review
Authors: Abo-Zahhad Mohammed , El-Malek Ahmed H. Abd , Sayed Mohammed S. , Gitau Susan Njeri
Published: June 2024

Retained surgical items (RSIs) pose significant risks to patients and healthcare professionals, prompting extensive efforts to reduce their incidence. RSIs are objects inadvertently left within patients’ bodies after surgery, which can lead to severe consequences such as infections and death. The repercussions highlight the critical need to address this issue. Machine learning (ML) and deep learning (DL) have displayed considerable potential for enhancing the prevention of RSIs through heightened precision and decreased reliance on human involvement. ML techniques are finding an expanding number of applications in medicine, ranging from automated imaging analysis to diagnosis. DL has enabled substantial advances in the prediction capabilities of computers by combining the availability of massive volumes of data with extremely effective learning algorithms. This paper reviews and evaluates recently published articles on the application of ML and DL in RSIs prevention and diagnosis, stressing the need for a multi-layered approach that leverages each method’s strengths to mitigate RSI risks. It highlights the key findings, advantages, and limitations of the different techniques used. Extensive datasets for training ML and DL models could enhance RSI detection systems. This paper also discusses the various datasets used by researchers for training the models. In addition, future directions for improving these technologies for RSI diagnosis and prevention are considered. By merging ML and DL with current procedures, it is conceivable to substantially minimize RSIs, enhance patient safety, and elevate surgical care standards.
High expression levels of centromere protein O participates in cell proliferation of human ovarian cancer
Authors: Si Li-hui , Sun Guang-chao , Liu Zi-wei , Gu Shi-yu , Yan Chu-han , Xu Jin-yuan , Jia Yan
Published: June 2024

Ovarian cancer is a common malignant tumor in women, with a high mortality rate ranking first among gynecological tumors. Currently, there is insufficient understanding of the causes, pathogenesis, recurrence and metastasis of ovarian cancer, and early diagnosis and treatment still face great challenges. The sensitivity and specificity of existing ovarian cancer screening methods are still unsatisfactory. Centromere protein O (CENP-O) is a recently discovered structural centromere protein that is involved in cell death and is essential for spindle assembly, chromosome separation, and checkpoint signaling during mitosis. The abnormal high expression of CENP-O was detected in various tumors such as bladder cancer and gastric cancer, and it participates in the regulation of tumor cell proliferation. In this study, we detect the expression abundance of CENP-O mRNA in different ovarian cancer cells ( ES-2, A2780, Caov-3, OVCAR-3 and SK-OV-3). The biological function changes of cell proliferation and apoptosis were detected and the role of CENP-O in ovarian cancer cell proliferation and apoptosis was explored by knocking down the expression of CENP-O gene. The results showed that CENP-O gene was significantly expressed in 5 types of ovarian cancer cell lines. After knocking down the CENP-O gene, the proliferation and cloning ability of ovarian cancer cells decreased, and the apoptosis increased. This study indicates that CENP-O has the potential to be a molecular therapeutic target, and downregulating the expression of CENP-O gene can break the unlimited proliferation ability of cancer cells and promote their apoptosis, providing a foundation and new ideas for subsequent molecular mechanism research and targeted therapy.
The Concussion, Exercise, and Brain Networks (ConExNet) study: a cohort study aimed at understanding the effects of sub-maximal aerobic exercise on resting state functional brain activity in pediatric concussion
Authors: Sharma Bhanu , Koelink Eric , DeMatteo Carol , Noseworthy Michael D. , Timmons Brian W.
Published: June 2024

Background

Recent scientific evidence has challenged the traditional “rest-is-best” approach for concussion management. It is now thought that “exercise-is-medicine” for concussion, owing to dozens of studies which demonstrate that sub-maximal, graded aerobic exercise can reduce symptom burden and time to symptom resolution. However, the primaryneuropathologyof concussion is altered functional brain activity. To date, no studies have examined the effects of sub-maximal aerobic exercise on resting state functional brain activity in pediatric concussion. In addition, although exercise is now more widely prescribed following concussion, its cardiopulmonary response is not yet well understood in this population. Our study has two main goals. The first is to understand whether there are exercise-induced resting state functional brain activity differences in children with concussion vs. healthy controls. The second is to profile the physiological response to exercise and understand whether it differs between groups.

Methods

We will perform a single-center, controlled, prospective cohort study of pediatric concussion at a large, urban children’s hospital and academic center. Children with sport-related concussion (aged 12–17 years) will be recruited within 4-weeks of injury by our clinical study team members. Key inclusion criteria include: medical clearance to exercise, no prior concussion or neurological history, and no implants that would preclude MRI. Age- and sex-matched healthy controls will be required to meet the same inclusion criteria and will be recruited through the community. The study will be performed over two visits separated by 24–48 h. Visit 1 involves exercise testing (following the current clinical standard for concussion) and breath-by-breath gas collection using a metabolic cart. Visit 2 involves two functional MRI (fMRI) scans interspersed by 10-minutes of treadmill walking at an intensity calibrated to Visit 1 findings. To address sub-objectives, all participants will be asked to self-report symptoms daily and wear a waist-worn tri-axial accelerometer for 28-days after Visit 2.

Discussion

Our study will advance the growing exercise-concussion field by helping us understand whether exercise impacts outcomes beyond symptoms in pediatric concussion. We will also be able to profile the cardiopulmonary response to exercise, which may allow for further understanding (and eventual optimization) of exercise in concussion management.

Trial registration

Not applicable.
Framework for implementing collaborative TB-silicosis activities in India: insights from an expert panel
Authors: Rupani Mihir P. , Nimavat Pankaj , Patel Yogesh , Shah Harsh D. , Sau Arkaprabha
Published: June 2024

Tuberculosis (TB) treatment is more challenging for patients with silicosis, as it complicates the diagnosis of both diseases and increases mortality risk. Silicosis, an incurable occupational disease, confounds the diagnosis of TB and vice versa, making it more difficult to accurately identify and treat either condition. Moreover, TB appears to accelerate the progression of silicosis. Exposure to silica dust, a common cause of silicosis, can also trigger latent TB to become active TB. This correspondence outlines a proposed framework for implementing collaborative TB-silicosis activities in India, aimed at improving early diagnosis and management for both diseases. An expert panel of medical professionals developed this framework through online consultations in October and November 2022. The panel's goal was to establish a consensus on integrating TB-silicosis activities, with a focus on early detection and proper management. The framework suggests testing all patients with silicosis for active TB and screening workers exposed to silica dust for latent TB infection. It also recommends that patients with TB who have a history of occupational exposure to silica dust should be tested for silicosis. Reliable diagnostic tools, such as chest X-rays, are emphasized, providing guidance on their use for both diseases. The proposed collaborative TB-silicosis framework offers a structured approach to identifying and managing these two diseases, contributing to the global goal of eliminating silicosis by 2030 and aligning with the World Health Organization’s targets for reducing TB incidence and mortality. It recommends specific strategies for implementation, including testing, referral systems, and workplace-based interventions. The framework also underscores the need for coordinated efforts among stakeholders, including the ministries of health, labor, industry, and environment. This correspondence provides valuable insights into how India can successfully implement collaborative TB-silicosis activities, serving as a model for other regions with similar challenges.
Association between perioperative flurbiprofen administration and acute kidney injury (AKI) in spine surgery: a retrospective cohort study
Authors: Liu Yongrong , Li Bo , Hang Lihua , Zhang Li
Published: June 2024

Background

The association between nonsteroidal anti-inflammatory drugs (NSAIDs) and postoperative acute kidney injury (AKI) remains controversial, with limited studies specifically examining flurbiprofen. Therefore, this research aimed to investigate the association between intraoperative flurbiprofen administration and postoperative AKI.

Methods

We retrospectively identified a cohort of patients at the Third Xiangya Hospital of Central South University. A total of 3882 adult patients undergoing spinal surgery between January 1, 2012, and July 31, 2018, were included and classified into two groups: those receiving flurbiprofen (50 or 100 mg once, 5 min after anesthesia start) and those not receiving flurbiprofen. The primary endpoint was the incidence of AKI.

Result

The flurbiprofen group (4.4%) had a lower incidence of AKI compared to the non-flurbiprofen group (6.5%, P < 0.001). After adjusting for potential confounding variables, the multivariable regression analysis showed that the flurbiprofen group had a 49% reduced risk of postoperative AKI (OR 0.51; 95% CI 0.31 to 0.82) compared to the non-flurbiprofen group. Subgroup analysis indicated that flurbiprofen injection was associated with a reduced incidence of postoperative AKI in patients without diabetes (OR 0.61; 95% CI 0.19 to 0.74), surgical times of 2–5 h (OR 0.54; 95% CI 0.23 to 0.75), and preoperative anemia (OR 0.57; 95% CI 0.21 to 0.74).

Conclusion

The study concluded that perioperative flurbiprofen treatment was associated with a lower risk of postoperative AKI in adult patients undergoing spinal surgery.
Flexural Strength of Light-Weight Steel Fiber Reinforced Concrete Containing Biodegradable LDHs Microparticles: Experimental Study and Multiscale Finite Element Model
Authors: Ramazani Pari , Moradi Shaghaghi Taleb , Farzam Masood , Afshin Hassan , Behnajady Mohammad A.
Published: June 2024

This study investigates the influence of LDHs (Layered Double Hydroxides) microparticles and steel fibers on the mechanical properties of lightweight concrete. Through a combination of experimental analysis and finite element modeling, the effects of LDHs and steel fibers on flexural strength and crack resistance were evaluated. The experimental results demonstrate a significant increase in flexural strength and toughness with the incorporation of LDHs microparticles and steel fibers. The finite element model corroborates these findings, highlighting the synergistic enhancement of mechanical properties due to LDHs and steel fibers. Additionally, the study discusses the frontier applications of LDHs in improving fracture characteristics and highlights the potential of hybrid reinforcement strategies in lightweight concrete. The findings reveal that both the quantity of microparticles and steel fibers significantly impact the concrete's residual strength. In scenarios without steel fibers, an optimal weight fraction of approximately 1 wt.% LDHs demonstrate a 39% increase in bearing capacity. Notably, under comparable conditions, the influence of LDHs microparticles on enhancing concrete mechanical characteristics appears to surpass the effects induced by steel fibers. However, at 2 wt.% LDHs usage, a decrease in load capacity by 3.3% is observed compared to the 1 wt.% LDHs configuration. This research provides valuable insights into optimizing concrete properties through novel material combinations and paves the way for future advancements in structural engineering.
Germline mutations of breast cancer susceptibility genes through expanded genetic analysis in unselected Colombian patients
Authors: Sierra-Díaz Diana Carolina , Morel Adrien , Fonseca-Mendoza Dora Janeth , Bravo Nora Contreras , Molano-Gonzalez Nicolas , Borras Mariana , Munevar Isabel , Lema Mauricio , Idrobo Henry , Trujillo Daniela , Serrano Norma , Orduz Ana Isabel , Lopera Diego , González Jaime , Rojas Gustavo , Londono-De Los Ríos Paula , Manneh Ray , Cabrera Rodrigo , Rubiano Wilson , de la Peña Jairo , Quintero María Catalina , Mantilla William , Restrepo Carlos M.
Published: June 2024

Background

In Colombia and worldwide, breast cancer (BC) is the most frequently diagnosed neoplasia and the leading cause of death from cancer among women. Studies predominantly involve hereditary and familial cases, demonstrating a gap in the literature regarding the identification of germline mutations in unselected patients from Latin-America. Identification of pathogenic/likely pathogenic (P/LP) variants is important for shaping national genetic analysis policies, genetic counseling, and early detection strategies. The present study included 400 women with unselected breast cancer (BC), in whom we analyzed ten genes, using Whole Exome Sequencing (WES), know to confer risk for BC, with the aim of determining the genomic profile of previously unreported P/LP variants in the affected population. Additionally, Multiplex Ligation-dependent Probe Amplification (MLPA) was performed to identify Large Genomic Rearrangements (LGRs) in theBRCA1/2genes. To ascertain the functional impact of a recurrent intronic variant (ATMc.5496 + 2_5496 + 5delTAAG), a minigene assay was conducted.

Results

We ascertained the frequency of P/LP germline variants inBRCA2(2.5%), ATM(1.25%), BRCA1(0.75%),PALB2(0.50%),CHEK2(0.50%),BARD1(0.25%),andRAD51D(0.25%) genes in the population of study. P/LP variants account for 6% of the total population analyzed. No LGRs were detected in our study. We identified 1.75% of recurrent variants inBRCA2andATMgenes. One of them corresponds to theATMc.5496 + 2_5496 + 5delTAAG. Functional validation of this variant demonstrated a splicing alteration probably modifying the Pincer domain and subsequent protein structure.

Conclusion

This study described for the first time the genomic profile of ten risk genes in Colombian women with unselected BC. Our findings underscore the significance of population-based research, advocating the consideration of molecular testing in all women with cancer.
In vivo stable 211At-labeled prostate-specific membrane antigen-targeted tracer using a neopentyl glycol structure
Authors: Suzuki Hiroyuki , Kannaka Kento , Hirayama Mizuki , Yamashita Tomoki , Kaizuka Yuta , Kobayashi Ryota , Yasuda Takahiro , Takahashi Kazuhiro , Uehara Tomoya
Published: June 2024

Background

Prostate cancer is a common cancer among men worldwide that has a very poor prognosis, especially when it progresses to metastatic castration-resistant prostate cancer (mCRPC). Therefore, novel therapeutic agents for mCRPC are urgently required. Because prostate-specific membrane antigen (PSMA) is overexpressed in mCRPC, targeted alpha therapy (TAT) for PSMA is a promising treatment for mCRPC. Astatine-211 (211At) is a versatile α-emitting radionuclide that can be produced using a cyclotron. Therefore, 211At-labeled PSMA compounds could be useful for TAT; however, 211At-labeled compounds are unstable against deastatination in vivo. In this study, to develop in vivo stable 211At-labeled PSMA derivatives, we designed and synthesized 211At-labeled PSMA derivatives using a neopentyl glycol (NpG) structure that can stably retain 211At in vivo. We also evaluated their biodistribution in normal and tumor-bearing mice.

Results

We designed and synthesized 211At-labeled PSMA derivatives containing two glutamic acid (Glu) linkers between the NpG structure and asymmetric urea (NpG-L-PSMA ((L-Glu)2 linker used) and NpG-D-PSMA ((D-Glu)2 linker used)). First, we evaluated the characteristics of 125I-labeled NpG derivatives because 125I was readily available. [125I]I-NpG-L-PSMA and [125I]I-NpG-D-PSMA showed low accumulation in the stomach and thyroid, indicating their high in vivo stability against deiodination. [125I]I-NpG-L-PSMA was excreted in urine as hydrophilic radiometabolites in addition to the intact form. Meanwhile, [125I]I-NpG-D-PSMA was excreted in urine in an intact form. In both cases, no radioactivity was observed in the free iodine fraction. [125I]I-NpG-D-PSMA showed higher tumor accumulation than [125I]I-NpG-L-PSMA. We then developed 211At-labeled PSMA using the NpG-D-PSMA structure. [211At]At-NpG-D-PSMA showed low accumulation in the stomach and thyroid in normal mice, indicating its high stability against deastatination in vivo. Moreover, [211At]At-NpG-D-PSMA showed high accumulation in tumor similar to that of [125I]I-NpG-D-PSMA.

Conclusions

[211At]At-NpG-D-PSMA showed high in vivo stability against deastatination and high tumor accumulation. [211At]At-NpG-D-PSMA should be considered as a potential new TAT for mCRPC.
Dual-trigger release of berberine chloride from the gelatin/perfluorohexane core–shell structure
Authors: Givarian Mahshid , Moztarzadeh Fathollah , Ghaffari Maryam , Bahmanpour AmirHossein , Mollazadeh-Bajestani Maryam , Mokhtari-Dizaji Manijhe , Mehradnia Fatemeh
Published: June 2024

Background

The development of smart nanocarriers that enable controlled drug release in response to internal and external triggers is an emerging approach for targeted therapy. This study focused on designing pH-sensitive, ultrasound-responsive gelatin/perfluorohexane (PFH) nanodroplets loaded with berberine chloride as a model drug.

Results

The nanodroplets were prepared using an emulsion technique and optimized by varying process parameters like homogenization rate, polymer concentration, surfactant, drug, and perfluorocarbon content. The optimal formulation yielded nanodroplets with a particle size of 281.7 nm, a drug encapsulation efficiency of 66.8 ± 1.7%, and a passive drug release of 15.4 ± 0.2% within 24 h. Characterization confirmed successful encapsulation and pH-responsive behavior. Ultrasound stimulation significantly enhanced drug release, with 150 kHz being more effective than 1 MHz in triggering acoustic droplet vaporization while minimizing heat generation. After 10 min of radiation, the optimal formulation showed 89.4% cumulative drug release. The nanodroplets displayed stability over 1 month at 4°C.

Conclusions

Overall, the dual-triggered nanodroplets demonstrate excellent potential for controlled delivery and targeted release of berberine chloride.

Graphical abstract
Evaluation of the biomarker potential of miR-650 and miR-663b in tumor tissues and plasma specimens of colon cancer patients living in northwest of Iran
Authors: Valizadeh Mehdi , Abdalla Jabar Kamal Mirza , Yazdanbod Abbas , Babaei Esmaeil
Published: June 2024

Background

Colorectal cancer (CRC) is considered as one of the most common malignancy and the fourth leading cause of cancer-related deaths, worldwide. Here, we aimed to investigate the expression of miR–663b and miR–650 in CRC tissue and plasma specimens.

Methods

In this case–control study, tumor specimens, non-tumoral adjacent tissues, and matched-plasma samples were obtained from forty patients with CRC living in the northwestern of Iran. Plasma of healthy patients was also collected as control. Total RNA was extracted from all specimens and studied by real-time PCR. Furthermore, the correlation between the expression of microRNAs and clinico-pathological features were also studied.

Results

Our data illustrated that miR-650 and miR-663b are down-regulated and up-regulated in tumor samples compared to non-tumoral margins, respectively (p < 0.001). However, the results did not show any significant difference in patient’s plasmas compared to controls. Further analysis disclosed that the expression of miR-663b is significantly associated with tumor size, lymph node metastasis, and tumor stage, while miR-650 is remarkably related to TNM stage, lymph node metastasis, distant metastasis, tumor size, and age. (p < 0.05) Furthermore, receiver operating characteristic (ROC) analyses revealed that miR-650 and miR-663b are potential biomarkers in differentiating CRC patients from healthy controls.

Conclusion

In conclusion, our data illustrated the potential of miR-650 and miR-663b as biomarkers in colorectal cancer. However, further studies are needed to confirm the employment of these microRNAs in the diagnosis and/or prognosis of colorectal malignancies.
Functionalized chitosan-G-poly caprolactone vaccine delivery system fabricated to display antigen–antibody immune complexes of Mycobacterium tuberculosis elicits immune response in Ex-vivo model
Authors: Rajadas Sam Ebenezer , Sounderrajan Vignesh , Prabhakaran Rajendran Amarnath , Agrawal Ragini , Jeyadoss Lavanya , Rajan Mariappan , Parthasarathy Krupakar , Harshavardhan Shakila
Published: June 2024

Background

Vaccine development against tuberculosis remains a global health imperative, necessitating robust immunogenicity and safety profiles. Nanoparticle-based delivery systems offer promising avenues to enhance vaccine efficacy while ensuring tolerability. This study explores the utilization of chitosan micelles as a delivery platform for immune complex vaccination against tuberculosis. Leveraging two key antigens of Mycobacterium tuberculosis, namely HspX and Mpt51, known for their relevance in latent tuberculosis and its co-infection with the human immunodeficiency virus, immune complexes were synthesized in vitro using antibodies raised against these antigens. The immune complexes were then conjugated onto chitosan micelles, characterized for their physicochemical properties, and evaluated for their biocompatibility and immunogenicity.

Results

Chitosan nanoparticles conjugated with either antigen or its immune complexes were synthesized as micelles and physicochemical characterizations confirm the formation of micelles without altering the polymer composition. These immune complex-conjugated chitosan micelles were found to be safe, exhibiting no significant hemolytic and cytotoxic activity even at a higher concentration of 400 µg/ml. Peripheral blood mononuclear cells upon stimulation with immune complex-conjugated chitosan micelles showed enhanced cellular uptake and one to two-fold increased expression of key immune markers—interferon gamma and CD-86.

Conclusions

These findings underscore the potential of chitosan nanoparticles as a versatile delivery platform for immune complex vaccination against tuberculosis. While limitations exist, such as including only two markers of immune modulation, this study lays a foundation for future investigations into immune complex vaccine potential in animal models. In conclusion, chitosan micelles carrying immune complexes of HspX and Mpt51 tuberculosis antigens exhibit promising immunogenicity, highlighting their potential as a platform for multi-antigenic vaccine components warranting further in vivo studies.
Neurological manifestations among Egyptian children with familial Mediterranean fever
Authors: Abu Shady Hend Mohamed , Osman Heba Taher , Elshennawy Sherine , Kamel Mona Ahmed
Published: June 2024

Background

Familial Mediterranean fever (FMF) is an auto-inflammatory periodic disorder resulting from mutations in the Mediterranean fever gene. Although it is considered a polyserositis disease, neurological-associated symptoms were also reported among different populations.

Aim of the work

To detect the frequency of neurological manifestations among Egyptian children with FMF and to investigate its association with various disease characteristics and various FMF gene mutations.

Patients and methods

This is an analytical cross-sectional study that enrolled 300 FMF children. Neurological manifestations such as headache, paresthesia, convulsions, tremors, breath-holding attacks, and syncope were reported. The dose, duration, and compliance with colchicine and the international severity scoring system for FMF (ISSF) were recorded. Serum amyloid A and gene mutations were recorded from patients’ files.

Results

The mean age of the patients was 10.35 ± 2.89 years; 158 (52.7%) were females, and 142 (47.3%) were males (F:M, 1.1:1), age at onset 4.67 ± 2.35 years and disease duration 3.28 ± 1.31 years. Genetic testing revealed positive MEFV gene mutation in 89.3%. Serum amyloid A was elevated in 33.7%. All patients were treated with colchicine, and 81.3% were compliant. Neurological manifestations were detected in 160 (53.3%) patients. Headache was the most common symptom in 136 (45.3%), followed by paraesthesia in 76 (25.3%). Epilepsy was present in 7 (2.3%) cases. Headaches were most frequent among patients with compound heterozygous mutation, severe ISSF scores, and poor compliance with colchicine.

Conclusion

Egyptian children with FMF present with various neurological manifestations. Headache and paresthesia were the most frequent, especially with the compound heterozygous mutations, severe ISSF score, and among colchicine non-compliant patients. Rheumatologists and neurologists should be aware of these manifestations and address the importance of disease control and adherence to colchicine to avoid or decrease these manifestations. Persistent unexplained headache or other neurological manifestations, in the presence of other symptoms suggestive of FMF or high serum amyloid A, should raise suspicion of FMF, and genetic testing should be requested. A multidisciplinary approach must be considered when managing these children.
The TAC-GReD trial: The combination of talazoparib and carboplatin in DNA damage repair deficient recurrent high-grade glioma.
Authors: Lecoultre Marc , Woo Peter Yat Ming , Leung Gilberto , Chow Shuk Wan Joyce , Ho Jason , Hong Ji Hyung , Chiang Chi Leung , Leung Dennis Kwok Chuen , Lam Tai-Chung , EL Helali Aya
Published: June 2024

2047

Background: Recurrent high-grade glioma (rHGG) has a dismal prognosis with limited treatment options. Given that a high proportion of these gliomas harbor deficiencies in the DNA damage repair (DDRd) pathway, this genomic occurrence may confer synergistic lethality and sensitivity to poly (ADP-ribose) polymerase (PARP) inhibitors. Therefore, we hypothesize that DDRd rHGG may be sensitive to the combination of a PARP inhibitor, talazoparib, and carboplatin. Methods: This is a prospective phase II, single-arm open-label biomarker stratified single-institution trial conducted in Hong Kong (NCT04740190). Tumor tissue was sent for comprehensive next-generation sequencing (C-NGS) to screen for genomic aberrations associated with the DDRd pathway. Patients with rHGG (WHO grade III-IV) and at least one pathogenic mutation in the DDR pathway were deemed eligible. Patients were initially treated with whole-brain radiotherapy (2 Gy/1 Fr) on C1D1. Starting at dose level 0, talazoparib (0.75mg on Days 1-4) and carboplatin (AUC 1.5 on Day 1), were administered weekly for a total of 18 cycles, followed by maintenance talazoparib. The primary endpoint was the 6-month progression-free survival (PFS-6). Results: 61 patients were screened and 33 patients with DDRd rHGG were enrolled, 23 males, 10 females, and a median age of 55 years (range: 29-70 years). 73% (n=24) had a baseline ECOG PS of 0-1. Among the recruited patients, 12% (n=4) were classified as WHO grade III, while the remaining 88% (n=29) were WHO grade IV. Dose level escalation was achieved in 27% (n=9) of the cohort. The 6-PFS was 29% (95% CI 16.2-51.9%) and the median PFS was 3.5 months (95% CI: 2.4-6.3 months). The OS at 3 and 12 months were 90.4% (95% CI 80.7-100%) and 30% (95% CI 17-53%), respectively. The most common grade 3-4 toxicities were neutropenia (21.2%, n=7), thrombocytopenia (18.2%, n=6) and anemia (9.1%, n=3). One patient developed a grade 4 thromboembolic event. Dose level reduction was implemented in 54% (n=18) of patients and treatment was terminated in 6.1% (n=2) due to toxicity. Conclusions: Talazoparib and carboplatin in a DDRd-enriched rHGG is feasible and tolerable. Additional analysis including correlation of biomarkers with long-term outcomes is underway. Clinical trial information: NCT04740190 .
High-dimensional longitudinal immune profiling uncovers a dual role of the CXCL9/CXCR3, CXCL13/CXCR5, and CCL11/CCL3 axis in the coupling of immune-related adverse events to immune checkpoint inhibitor response.
Authors: Obeid Michel , Joo Victor , Daoudlarian Douglas , Bartolini Robin , Bouchaab Hasna , Latifyan Sofiya , Mederos Nuria , Abdelhamid Karim , Mosimann Valérie , Ferahta Nabila , Shabafrouz Keyvan , Pantaleo Giuseppe , Peters Solange
Published: June 2024

2512

Background: Additional characterization is required to understand the immune network signatures and immunophenotypes that link immune-related adverse events (irAEs) to immune checkpoint inhibitor (ICI) therapy responses in cancer patients. Methods: A comprehensive immune profiling analysis was conducted on whole blood and peripheral blood mononuclear cells (PBMC) from 165 oncology patients with various irAEs, including colitis (n=64), myocarditis (n=19), pneumonitis (n=25), arthritis (n=24), and cytokine release syndrome CRS (n=33), and compared to a cohort of 219 cancer patients prior to ICI treatment. Results: Following ICI therapy on cycle 2 day 1 (C2D1), we observed significant increases in IL-6, CCL2, CXCL9, CXCL10, and CXCL13 levels preceding irAEs. CXCL9 was specifically upregulated during the development of colitis, arthritis, CRS, and myocarditis, while CXCL13 increased only in CRS, and CCL3 only in myocarditis and CRS, with no CCL11 upregulation in any irAE. High levels of CXCL9, high CCL11 and low CXCL13 strongly correlated with improved oncologic outcomes in different irAEs. Compared to other cluster, in the high CXCL9 cluster, 5-year overall survival (OS) was significantly improved (HR = 10.26 [95% CI, 1.27-82.82], p = 0.029) in colitis (n=20), in CRS (n=21) (HR = 6.45 [95% CI, 1.60-25.99], p = 0.009), and in arthritis. In the high CCL11 cluster, 5-year OS was significantly improved in pneumonitis (n=15), (HR = 4.04 [95% CI, 1.05-15.46]). Conversely, in myocarditis, the high CXCL13 cluster (n=9) was associated with decreased 2-year OS (HR = 6.05 [95% CI, 1.03-35.48], p = 0.046). It is important to note that the CXCL9-driven immunophenotypes were characterized by low IL-6. Notable observations include CD38 upregulation and large-scale activation of CD8 memory subsets during ICI therapy, concomitant with increased circulation of immature neutrophils at the onset of irAEs diagnosis. This event may increase the migration of TCRγδ, NK, DC, and CD8 cells to tumor sites through CXCR3/CXCL9 interactions. Conclusions: This study unravels intricate connections between immune activation and tumor response. CXCL9, CCL11, and CXCL13 emerge as pivotal biomarkers bridging the gap between ICI therapy effectiveness and distinct irAEs-associated immunophenotypes.
Evaluation of mixed response in tumor size and survival in patients with rare cancers treated with dual checkpoint inhibitor therapy (DART SWOG S1609).
Authors: Chae Young Kwang , Dietrich Eliana , Othus Megan , Chung Liam IL Young , Kim Hye Sung , Ryan Christopher W. , Blanke Charles D. , Patel Sandip Pravin , Kurzrock Razelle
Published: June 2024

2514

Background: RECIST criteria evaluate changes in tumor burden and have been utilized in cancer research for decades. Changes in the sum of maximum diameters of “target” lesions are used to designate patients into response categories, including complete response, partial response, stable disease, and progressive disease. However, not much is known about the implications of mixed response, where lesions within a patient show contrasting responses to systemic treatment. Here we evaluate the data from the Dual Anti-CTLA-4 and Anti-PD-1 Blockade in Rare Tumors (DART) SWOG S1609 to investigate the association between mixed response and survival among patients treated with dual checkpoint inhibitor therapy. Methods: A total of 796 patients were enrolled on the S1609 DART trial, a basket trial evaluating ipilimumab plus nivolumab across solid rare tumor subtypes. All patients had RECIST-measurable disease at the study entry. Patients were excluded from the analyses due to: ineligibility, n=47; not receiving any protocol therapy, n=23; death before day 65 (landmark for analysis based on first scan), n=86; 1 target lesion, n=153. Thus, 487 patients were analyzed. A 5mm cut-off for increase/decrease in lesions was used to define a mixed response. Cox regression models were used to evaluate associations between survival (landmarked at day 65, stratified by basket) and response category (reference of Stable Disease). Results: 6 groups were identified among the 487 patients: no lesions changed more than 5 mm (n = 105), all lesions increased more than 5mm (n = 69), all lesions decreased more than 5mm (n = 39), one+ lesion increased more than 5mm and one+ lesion decreased more than 5 mm (n = 24), one+ lesion increased more than 5mm and one+ lesion did not change more than 5 mm (either direction) (n =155), one+ lesion decreased more than 5mm and one+ lesion did not change more than 5 mm (either direction) (n =95). Hazard ratios and median survival (mOS) are shown (Table). Conclusions: This is the first evaluation of the association between mixed response and survival outcomes among patients with various tumors receiving dual checkpoint therapy. Our results suggest that survival outcomes are driven by the “worst” performing lesion; in other words, having an increase in any lesion is associated with worse outcomes, even if not all lesions increase. [Table: see text]
Effect of fecal transplantation on patient reported outcomes after immune checkpoint inhibitor colitis.
Authors: Shatila Malek , Varatharajalu Krishnavathana , Shen Shu-En , Herrera Mary , Wang Xin Shelley , Thomas Anusha , DuPont Herbert L. , Wang Yinghong
Published: June 2024

2517

Background: The use of fecal microbiota transplantation (FMT) has traditionally been reserved for the treatment of recurrent Clostridioides difficile infections (CDI). As the gut microbiome has been increasingly acknowledged to play a role in a variety of bodily processes, FMT has seen its application extended to other gastrointestinal disorders. Immune-mediated colitis (IMC) is a similar entity to inflammatory bowel disease and arises as a side effect of immune checkpoint inhibitor therapy to stimulate the immune response. Treatment of IMC is mostly limited to immunosuppressants e.g. corticosteroids, infliximab, and vedolizumab. Cases refractory to such medications pose a significant challenge. FMT has been shown to be a successful treatment in refractory IMC in small case series, further large studies are needed to determine its efficacy. Methods: We measured the efficacy of FMT for refractory IMC among 37 patients via chart review and clinical assessment and patients’ reported outcome (PRO) via established MD Anderson Symptom Inventory (MDASI). Among them, 9 patients had concurrent CDI as well at the time of diagnosis. Results: Fifty-nine patients were included in our study. Most patients had a peak diarrhea grade ≥ 3 (94.9%) and colitis grade ≥ 2 (91.5%). Ulcerous (26, 44.1%) and non-ulcerous (21, 35.6%) inflammation were the predominant endoscopic findings. Fifty-seven (96.6%) patients received corticosteroids, and 54 patients (91.5%) received add-on infliximab or vedolizumab. IMC symptom response was 84.7% after FMT with median time to response of 4 days. The transient complication rate is 30.5% at 7 days and 18.6% at 30 days. Response rate among the 50 patients without concurrent CDI was 86.0%. Fifty (84.7%) patients demonstrated clinical remission by the end of the study period, and 11 (18.6%) were able to resume ICI treatment, and among them, 9 patients remained in remission. A total of 10 patients (16.9%) in our cohort developed recurrent colitis after FMT requiring immunosuppression; 3 of these recurrent cases were triggered by ICI resumption. On the PRO analysis, we observed a favorable trend of significant patient-reported symptom reduction on diarrhea (61% to 11%, p<0.01) and abdominal bloating (36% to 7%, p<0.05) during 12 weeks after FMT. There was a 49.4% reduction of moderate to severe symptoms with only 44% of patients reporting such symptoms after 12 weeks (down from 89%, p<0.01). Conclusions: FMT may serve as a potential treatment option in IMC refractory to standard treatment to avoid long-term steroid dependency and immunosuppression. It is effective to maintain IMC remission with a low complication rate. The role of the gut microbiome in cancer and the implications for FMT remain uncertain and need further elucidation. Clinical trial information: NCT03819296 .
First-in-human study of ZGGS18, a dual specific antibody targeting VEGF and TGF-β, as monotherapy in patients with advanced solid tumors.
Authors: Zhao Chuan Hua , Shi Jianhua , Chai Xiaoli , Tan Lirong , Wu Lihua , Zheng Li , Cao Dan , Mai Gang , Fan Lianlian , Mi Yanjun , Wang Jufeng , Han Xinghua , Xu Jianming
Published: June 2024

2523

Background: ZGGS18 is a bifunctional antibody fusion protein, which consists of a monoclonal antibody (optimized Bevacizumab) against vascular endothelial growth factor A (VEGF-A) and an engineered human transforming growth factor-β receptor II extracellular domain (TGF-β RII ECD). It can specifically bind VEGF-A and "capture" TGF- β isomers. It plays a synergistic role in inhibiting tumor growth, such as inhibiting tumor angiogenesis and reducing tumor metastasis. In addition, ZGGS18 can also improve and regulate the tumor microenvironment, so it can enhance the tumor-killing effect in combination with anti-PD-(L) 1 antibody and other tumor immunotherapeutic drugs. We conducted a Phase 1 clinical study to assess the tolerability and safety of this drug. Methods: It was a dose-escalation study. Subjects were patients with advanced solid tumors who failed to the available standard treatments. The dose groups were set from 0.3 to 20 (0.3, 1, 3, 6, 10, 15, 20) mg/kg, intravenous infusion, once every 2 weeks. An accelerated titration design (ATD) was utilized in the first three dose groups and a standard "3+3" design was used in the rest doses. The first 28-day period was defined as the dose-limiting toxicity (DLT) observation period. Subjects could continue to receive ZGGS18 until treatment discontinuation criteria were met. Tumor response was assessed by RECIST1.1. Results: At the data cut-off (4 Jan 2024), 21 patients (14 males and 7 females) were enrolled, with a median age of 60 years. 13 (61.9%) of them received at least 2 lines of antineoplastic therapies. 76.2% (16/21) of patients experienced treatment-related adverse events (TRAEs) and 19.0% (4/21) of patients had grade 3 TRAEs (1 Lower gastrointestinal hemorrhage in the 10 mg/kg, 1 pneumonia in the 15 mg/kg, 1 anemia in the 20 mg/kg, and 1 blood fibrinogen decreased in the 20 mg/kg dose group). Wherein, the grade 3 blood fibrinogen decreased was a DLT event. The most frequent TEAEs (with incidence >10%) were anemia, lymphocyte count decreased, gingival bleeding, epistaxis, hypoalbuminemia, proteinuria, hypocalcemia, hypokalemia, fever, aspartate aminotransferase increased, bile acids increased, and disease progression. There is one subject with endometrial carcinoma who has received 19 infusions of ZGGS18 and is remaining in this study, and another subject with rectal carcinoma had 29.65% tumor shrinkage at week 12. The Cmax and AUC increased from 0.3-20 mg/kg approximately in dose proportion. Conclusions: ZGGS18 demonstrated its safety and tolerability in this dose-escalation study, along with a good PK profile, providing a good basis for monotherapy and/or combination therapy for future use. Clinical trial information: NCT05584800 .
Tocilizumab for advanced non-small cell lung cancer with concomitant inflammatory cachexia: A single-centre study.
Authors: Du Yang , Liu Xiao-Yian , Pan RuiLi , Zhang Xiao-Tong , Si Xiao-Yan , Chen Minjiang , Wang Mengzhao , Zhang Li
Published: June 2024

2647

Background: Cancer cachexia significantly contributes to morbidity and mortality in patients with non-small cell lung cancer (NSCLC). Inflammatory pathways mediated by interleukin-6 play a crucial role in the development of cancer cachexia. This study aimed to investigate the use of tocilizumab, an anti-interleukin-6 receptor inhibitor, in the management of NSCLC with coexisting inflammatory cachexia. Methods: Data were collected from patients with NSCLC and concurrent inflammatory cachexia who received either tocilizumab plus anti-tumour therapy or anti-tumour therapy alone. The primary endpoints were overall survival (OS) and improved modified Glasgow Prognostic Score (mGPS) at week 12, while secondary endpoints included changes from baseline over 12 weeks in body weight, albumin, C-reactive protein and mGPS. Qualitative improvements in patient self-rated appetite and fatigue were reported as exploratory analysis. Results: The study included 49 patients diagnosed with NSCLC and coexisting inflammatory cachexia, of which 26 received tocilizumab in combination with anti-tumour therapy, and 23 received anti-tumour therapy alone. The tocilizumab group demonstrated a significantly longer median OS compared to the control group (15.1 vs. 3.2 months; hazard ratio 0.18, 95% confidence interval 0.08-0.38; p < 0.001). The rate of patients surviving with mGPS improvement at week 12 was significantly higher in the tocilizumab group than in the control group (OR 168.7, 95% CI 16.3-1746.5; p < 0.001). Over the 12-week period, significant improvements were observed in body weight, albumin, C-reactive protein, and mGPS in the tocilizumab group compared to the control group. Additionally, the tocilizumab group displayed significantly higher rates of improvement in appetite and fatigue. The incidence of grade 3 or higher adverse events was 34.6% in the tocilizumab group compared to 78.3% in the control group. Tocilizumab-related adverse events were observed in three patients (11.5%), including two cases of neutropenia and one case of skin and subcutaneous tissue infection. Conclusions: Tocilizumab demonstrated significant benefits in survival and various clinical parameters, including body weight, albumin, C-reactive protein, mGPS, and symptom burden in patients with NSCLC and concurrent inflammatory cachexia. Given the existing unmet medical need for effective interventions for cancer cachexia, tocilizumab may be considered as a potential treatment option.