bluuebunny/crossref_metadata_2025 huggingface dataset:
Genomic profiling of lung adenocarcinoma and squamous carcinoma in Indian patients: Implications for precision oncology.
Authors: Prabhash Kumar , Kumar Prashant , Jha Prerana , Joshi Asim , Mishra Rohit , Limaye Sewanti , Kanakasetty Govind Babu , Batra Ullas , Malik Prabhat Singh , Menon Nandini Sharrel , Shah Minit Jalan , Patil Vijay Maruti , Rauthan Amit , Kuriakose Moni , Noronha Vanita , Venkataramanan R
Published: July 2024

e20599

Background: Lung cancer, the leading cause of cancer related mortalities, remains a significant global health burden. Despite advances in next generation sequencing technologies, the genomic landscape of non-small cell lung cancer (NSCLC) in the Indian patients remains underexplored. In this study, we aimed to elucidate the genomic landscape of lung adenocarcinoma and squamous carcinoma among Indian patients using targeted sequencing data of over 400 lung cancer patients. Methods: Utilizing targeted sequencing of 50 established cancer-related genes, we conducted a comprehensive analysis of the genomic alteration profiles in 325 lung adenocarcinoma and 81 lung squamous carcinoma samples from Indian patients. Further, we employed robust statistical methodologies to delineate correlations between genomic alterations and clinical characteristics including age, gender, extent of disease, habits and PD-L1 status. Furthermore, our investigation revealed distinctive genomic signatures of NSCLC specific to the Indian population through comparative analyses across various ethnicities. Results: EGFR mutations were detected in 45.8% of lung adenocarcinoma and a notable 18% of lung squamous carcinoma cases among Indian patients, showing significant prevalence among females and non-smokers. Alongside EGFR, lung adenocarcinoma patients exhibited frequent alterations in TP53 (27.4%), ALK (11.4%), and KRAS (10.2%), while lung squamous carcinoma cases predominantly showed mutations in TP53 (40.7%), PIK3CA (17.3%), and CDKN2A (8.6%). Remarkably, 68% of lung adenocarcinoma cases deemed eligible for NCCN-approved targeted therapies. Additionally, it was observed that 60% of PD-L1-negative squamous carcinoma patients harbored TP53 alterations, indicating intriguing therapeutic implications. Overall, we observed alterations in 88% lung adenocarcinoma and 70% lung squamous carcinoma patients. Conclusions: Our study unveiled distinct genomic variations present in both adenocarcinoma and squamous carcinoma patients from India, revealing crucial insights for precision medicine and clinical management of lung cancer. Our findings provide a significant lead for designing clinical trials aimed at evaluating EGFR inhibitors in lung squamous carcinoma patients, potentially expanding therapeutic options for Indian lung cancer patients.
Spectrum of HER2 alterations in NSCLC: Comparative analysis of tissue and liquid biopsies in lung cancer.
Authors: Choudhary R. K. , Koppaka Deepak , Vaid Ashok K , Kulkarni Shriniwas Subhash , Bose Chirantan , Morzaria Dr Disha , Apurwa Sachin , Vijayan Poornima , Bhatt Amit Dilip , Ranade Anantbhushan , Page Raymond , Patil Darshana , Akolkar Dadasaheb , Limaye Sewanti
Published: July 2024

e20602

Background: Non-Small Cell Lung Cancer (NSCLC) exhibits a spectrum of molecular alterations that play a crucial role in understanding its heterogeneity and tailoring targeted therapies. Among these alterations, HER2 aberrations have gained significance as potential therapeutic targets. This study aims to explore the diversity of HER2 changes in NSCLC through tissue and liquid biopsies, providing valuable insights into the feasibility and accuracy of either method. Methods: Data from next generation sequencing of 799 tissues and 1380 liquid biopsy specimens was retrospectively analyzed. The study sought to elucidate the prevalence of HER2 alterations with these two methodologies, evaluating their respective strengths and limitations in detecting HER2 changes in NSCLC. Results: HER2 mutations were identified in 2.1% (17/799) of tissue, mirroring the prevalence observed in the TCGA cohort (2%). The liquid biopsy cohort identified Her2 mutations with similar prevalence and was positive for Her2 mutations in 2.2% (30/1380). Within Her2 mutations, HER2 exon 20 insertion mutations emerged as the predominant variant, accounting for all variants in tissue samples and 93.3% (28/30) in liquid biopsies. The most frequent HER2 exon 20 variant was p.Y772_A775dup variant (76.5% in tissue, 71.4% in liquid biopsy), followed by p.E770_A771insAYVM (17.6% in tissue and 7.1% in liquid). Less frequent HER2 mutations included p.G776delinsLC, p.G776delinsVC, p.V777_G778insGSP, p.A775_G776insYVMA. HER2 amplification was detected in 1.4% (5/352) of tissue and 1.3% (8/617) of liquid biopsy samples; concurrent HER2 mutation and Her2 amplification were detected in 3 liquid biopsy samples. 11/60 cases had concurrent targetable alterations in other targetable genes. Most common concurrent alterations were in EGFR followed by KRAS. Concurrent EGFR sensitizing alterations were observed in 7 patients ( 6 EGFR Exon 19 deletion and one EGFR L858R). Only 2/7 patients showed concurrent EGFR/HER2 alterations at baseline, the remaining 5/7 patients had received prior EGFR TKI therapy. Conclusions: Our results demonstrate equivalent Her2 alteration detection rate with liquid biopsy as compared to tissue molecular profiling in NSCLC. Our results support utility of liquid biopsy for Her2 profiling in the primary setting as well as to detect acquired Her2 alterations like in patients post EGFR-TKI therapy. It highlights that HER2mutations coexist with HER2 amplification in subset of advanced NSCLC patients. [Table: see text]
Unleashing deep features and radiomics to enhance best overall response prediction to immunotherapy in advanced non-small cell lung cancer.
Authors: Urbanos Gemma , Jiménez Pastor Ana , Lozano-Montoya Jose , Bellvís Bataller Fuensanta , Weiss Glen J. , Alberich-Bayarri Angel
Published: July 2024

e20611

Background: Predicting immunotherapy response in advanced non-small cell lung cancer (NSCLC) through non-invasive means could be a groundbreaking advancement. Deep features extracted from medical images by deep Convolutional Neural Networks (CNNs) along with radiomics have demonstrated promising results in different oncologic diseases. However, the method for extracting these deep features influences the predictive capabilities of the model. Methods: A retrospective analysis of a multicenter study was conducted in advanced NSCLC patients with high PD-L1 expression with the aim of developing an imaging features-based model for the prediction of best overall response (BOR) to a checkpoint inhibitor immunotherapy. All visible lung lesions, beyond RECIST 1.1, were manually segmented in baseline CT scans. Radiomics features were extracted at lesion-level, and various preprocessing methods and CNN architectures were tested for deep features extraction. Radiomics and deep features were harmonized using ComBat methodology. A distinctive feature signature was created for each patient by calculating the mean across all lesions. Using this data, machine learning models were trained to predict treatment response, specifically distinguishing between complete response (CR) and partial response (PR) from stable disease (SD) and progressive disease (PD). The study compared the performance of different deep features extraction methods and assessed shapley additive explanations (SHAP) values of radiomics for interpretability. Results: In the cohort of 116 patients (mean age: 67, 93% ever-smokers, 73% male), 1024 to 5475 quantitative imaging features per lesion were extracted. Among these patients, 67 patients were CR+PR, and 49 were SD+PD. The top-performing predictive model, trained with radiomics and deep features from a deep convolutional autoencoder, achieved an average AUC of 85%. SHAP values showed that impactful radiomics features were correlated with intensity changes in adjacent pixels describing the tumor heterogeneity, along with shape features potentially associated with malignancy. Ultimately, combining both features demonstrated statistical significance, leading to a performance improvement of ~2-5% compared to models exclusively using deep features. Conclusions: Diverse techniques for extracting deep features were evaluated, revealing autoencoder training as the most effective strategy for predicting immunotherapy response. Consequently, the findings suggest that employing deep learning to extract imaging features from baseline CT scans, combined with radiomics, represents a promising non-invasive approach for the predicting immunotherapy outcomes in advanced NSCLC patients.
Ethnic disparities in biomarker testing of patients with metastatic NSCLC in the United States: A real-world analysis.
Authors: Jayram Diya , Bellur Shreyas S , Ozair Ahmad , Ahmad Shahzaib , Ganiyani Mohammad Arfat , Khosla Atulya Aman , McCracken Andrea , Marada Suresh , Hurmiz Charlie , Bowman Steven , Ahluwalia Manmeet Singh
Published: July 2024

e20617

Background: National Comprehensive Cancer Network guidelines recommend biomarker testing prior to intervention in metastatic non-small cell lung cancer (mNSCLC). However, biomarker testing remains low, particularly in minorities, especially when targeted therapy against actionable driver mutations improves outcomes and quality of life significantly. We sought to determine testing rates and assess disparities between Hispanic and non-Hispanic Whites. Methods: A retrospective cohort study was conducted in accordance with "strengthening the reporting of observational studies in epidemiology" (STROBE) guidelines. All Hispanic and non-Hispanic White patients across a US oncology-focused hospital consortium (Guardian Research Network) were identified from 01/2018 to 01/2023. Socio-demographic details, clinical profiles, and details related to biomarker testing, treatment, and clinical outcomes were extracted. We also ascertained the area deprivation index (ADI) based on zip code as a surrogate for socio-economic stratification. We grouped patients into validated quintiles of ADI. We extracted testing details of the most common driver mutations – EGFR, ALK, KRASG12C, and PDL1. Data were analyzed using descriptive and inferential statistics. Results: Out of 4898 eligible patients with mNSCLC, 9.89% (n = 484/4898) were Hispanic, and 90.11% (n = 4414/4898) were non-Hispanic Whites. Overall testing rates for EGFR, ALK, KRASG12C and PD-L1 were 36.07% (n = 1767/4898), 33.60% (n = 1646/4898), 3.76% n = 184/4898) and 48.42% (n = 2372/4898). EGFR and ALK testing revealed significant differences showing reduced testing in the non-Hispanic White population (Table 1.) Multivariate logistic regression revealed no significant association between ADI, ethnicity and biomarker testing. Four hundred and eighty-three individuals underwent biomarker testing but did not receive treatment. Forty-three percent (n = 205/483) were alive at the time of data extraction, with 5.18% (n = 25/483) identified as Hispanic. Conclusions: Our analysis reveals that biomarker testing remains low in patients with mNSCLC, showing decreased testing rates of EGFR and ALK in non-Hispanic Whites when compared to Hispanic Whites. Purposeful strategies such as education and testing awareness campaigns are warranted to overcome low testing rates in patients diagnosed with mNSCLC.[Table: see text]
Revolutionizing global hematology-oncology education: Assessing the two-year impact of a digital platform on socioeconomic equity and inclusivity against gender disparities.
Authors: Leyfman Yan , Wilkerson William B. , Cortiana Viviana , Gambill Jade , Menon Gayathri P. , Joshi Muskan , Heller Elizabeth Jean , Smith Keira , Coloma Helena S. , Balasubramanian Maduri , Zahid Emad B. , Van de Kieft Alexandra , Chorya Harshal , Abbas Rabab H. , Ghazal Jenna Fadi , Bowers Blaise , Azeez Ahmed , Park Chandler H.
Published: July 2024

e21000

Background: Social media has transformed the global exchange of knowledge, with 77.4% of cancer patients relying on it as a primary source of information especially in resource-limited areas. Given that a third of social media posts contain misinformation that can have negative ramifications, MedNews Week (MNW) was developed as a digital platform featuring presentations by global authorities to enhance global oncology education through its freely accessible programming. In light of the gender disparity in speakers at scientific symposia, where females represent <30%, MNW strived to combat gender inequity by featuring them in equal proportion to males. The goal of this study was to evaluate the ability of MNW’s virtual oncology education platform to combat socioeconomic (SE) education inequity while promoting gender inclusivity. Methods: From January 2022 to 2024, MNW hosted 36 distinguished global oncology leaders as Keynote Speakers (Mean H-index=50.09). Data on viewership and outreach were collected from MNW's social media accounts. A mixed-method approach was employed to determine audience and speaker demographics, and engagement. Results: MNW achieved a Healthcare Social Score amongst the top 0.07 percentile of global healthcare influencers on Twitter. Over the past year, MNWoncology programming experienced a 10.5-fold increase in mean attendance, reaching 743,991 people in 95 countries globally, with 23 classified as low-to-middle SE status. In 2023, MNW followers exhibited a female predominance (48.8%), mainly from non-healthcare fields (60.0%). MNW showcased gender parity among oncology keynote speakers, with female lecturers drawing similar attendance as males (p=0.89, two-tailed unpaired t-test). Conclusions: MNW has established a growing digital platform, while removing financial barriers to effectively engage lay audiences, particularly in underserved regions. MNW's commitment to empowering female speakers exemplifies its dedication to inclusivity in a historically imbalanced field. This underscores MNW's success in fostering inclusivity, by driving engagement of those traditionally underserved, and positively impacting oncology education globally. [Table: see text]
Empowering tomorrow's oncologists: Establishing an oncology student interest group to propel careers in cancer care.
Authors: Singh Abhishek , Jain Nidhi , Chauhan Aditya , Obulareddy Sri Usha Jeevani , Seetharaman Kala
Published: July 2024

e21014

Background: In cancer care, smaller academic community hospitals play a crucial role in serving local and underserved populations. However, these institutions often need help providing comprehensive mentorship opportunities for internal medicine residents interested in pursuing careers in oncology. Limited resources, smaller clinical teams, and a focus on delivering patient care often precede research and scholarly activity. To help with this goal, ASCO has a program known as OSIG, which stands for Oncology Student Interest Group, which provides resources for medical students and residents to meet regularly, network with academic faculty, learn about cancer care, and learn about opportunities in oncology. Methods: This observational study employed a cross-sectional survey design to investigate the perceived benefits of establishing an oncology interest group among internal medicine residents. The survey aimed to collect quantitative and qualitative data on residents' opinions regarding the potential advantages, challenges, and overall impact of initiating an ASCO affiliated oncology-focused student interest group [OSIG] within an academic community hospital internal medicine residency program in Worcester, MA. Results: Of the total strength of 75 residents, a total of 17 residents were surveyed for this project, with 7 [41%] female, and 10 [59%] male residents. 6 [35%] PGY1, 2 [11%] PGY2, and 9 [52%] PGY3 residents participated in the survey. 15 [88%] residents were 'very likely' interested in a career in oncology. 16 [94%] residents replied that participating in the oncology interest group meetings enhanced their understanding of cancer care and treatment options. 17 [100%] replied that networking with oncology professionals was 'very important' for their career development. 15 [88%] replied that the support provided by the OSIG helped find them mentorship opportunities 'to a large extent'. 15 [88%] replied that the oncology interest group could assist in clarifying their career goals within oncology by 'a lot'. The survey included two questions with room for subjective answers aboutpotential challenges or concerns, and additional thoughts, suggestions, or comments. Conclusions: The results indicate that residents recognize the potential of an ASCO-affiliated interest group to significantly enhance their understanding of cancer care and treatment options, providing a valuable supplement to their internal medicine training. The prospect of networking with established oncologists by spurring collaboration among residents, attending national and local conferences in the field is deemed crucial for career development, as is the belief that mentorship opportunities within the interest group could play a pivotal role in shaping future careers in oncology.
A multicenter, single-arm, open-label phase II study to evaluate the efficacy and safety of YH003 in combination with pembrolizumab and nab-paclitaxel in the first-line treatment of patients with unresectable/metastatic mucosal melanoma.
Authors: Chen Yu , Zhang Xiaoshi , Ding Ya , Jiang Yu , Chen Jing , Pu Xingxiang , Ren Xiubao , Zhang Weizhen
Published: July 2024

e21520

Background: Mucosal melanoma therapy remains a formidable challenge especially in Asia. Although several therapies are available for skin type of melanoma, the efficacy of mucosal melanoma is not satisfactory. YH003, a humanized agonistic anti-CD40 monoclonal antibody specifically recognizes and agonizes CD40 to enhance immune responses, has demonstrated good safety and promising antitumor activity in Phase I clinical studies in patient with ocular melanoma. Here, we report the results of the phase II study of YH003 in combination with pembrolizumab and nab-paclitaxel in the first-line treatment of patients with unresectable/metastatic mucosal melanoma. Methods: Patients with unresectable/metastatic mucosal melanoma were enrolled and received 0.3 mg/kg YH003, 200 mg pembrolizumab and 200 mg/m2 of nab-paclitaxel iv, every 21 days. The treatment continued for 12 months if subject was deriving an ongoing clinic benefit. The primary endpoint was overall Response Rate (ORR) by investigator’s assessment per RECIST 1.1. Results: A total of 20 patients were enrolled and had at least 1 evaluable post-treatment tumor assessment, the unconfirmed ORR was observed in 7 patients (35.0%), with 7 partial responses (PR). 7 patients (35.0%) had stable disease (SD), and the Disease Control Rate (DCR) was 70.0%. The mOS was not reached, mPFS was 4.11 months. The grade 3 or above TEAE that occurred in the 20 patients were 30.0% (6/20). There is no significant safety signal from the study. Conclusions: The results of the phase II study have shown that YH003 in combination with pembrolizumab and nab-paclitaxel, as 1L treatment in patients with unresectable/metastatic mucosal melanoma have promising antitumor activity and response durability and well tolerated. Clinical trial information: NCT05420324 .
Risk score stratification of cutaneous melanomas based on whole slide images using deep learning.
Authors: Bossard Céline , Salhi Yahia , Quereux Gaelle , Khammari Amir , Salhi Sanae , Lavoine Eric , Chetritt Jérôme
Published: July 2024

e21573

Background: Predictive and prognostic biomarkers represent the cornerstone of clinical oncology. Improving the prognostication of melanoma is needed to select patients for effective adjuvant therapies. Taking into account that tumor tissue contains a large amount of clinically relevant hidden information that is not fully exploited, we applied a weakly-supervised deep-learning approach on H&E-stained whole-slide image (WSI) to directly predict 5-year survival outcomes in melanoma patients. Methods: We designed a deep neural (DL) network that extracts features from no-padding patches of WSI (tiles of size 512x512 pixels) using a self-supervised learning framework as well as from the tumor region. These features are then fed along with survival information into the deep learning fusion network assigning a survival risk score to each WSI. The model was trained and validated on 195 cases of primary melanoma diagnosed between 2015 and 2017 originating from the IHP Group and the French RICMel melanoma database. Performance was evaluated using a cross-validation and cross-testing framework as well as on an external set of 238 cases from the TCGA database. Concordance index (c-index) was used as a metric to assess the performance of the proposed algorithm. Results: For the prediction of survival, the proposed pipeline yielded c-index of 0.76 and 0.66 for the IHP Group cohort and TCGA dataset respectively. Furthermore, the model is able to significantly discriminate between the 2 groups of patients, with a good and a poor prognosis in terms of overall survival (p-value < 0.001 for IHP and p-value = 0.01 for TCGA). Also, the proposed score is statistically significant when added to a multivariate cox model incorporating the classic prognosis factors (p-value < 0.005) and allows to reach a c-index of 0.81 over the discovery cohort. Conclusions: This infrequent weakly-supervised deep-learning approach to HE images analysis has the advantage of leaving the feature selection entirely to the deep network, and so discover new morphological biomarkers. By this way, it could have in the near future the potential to accelerate and improve the clinical decision-making process in the field of melanoma. Also, these findings will undoubtedly open room for substantial applications with economic and treatment delay fallouts.
The efficacy and safety of ruxolitinib as an add-on therapy to corticosteroids for patients with severe checkpoint inhibitor pneumonitis.
Authors: Xu Yan , Huang Hui , Gao Xiaoxing , Liu Xiaoyan , Chen Ruxuan , Chen Minjiang , Zhao Jing , Zhong Wei , Gao Junzhen , Wang Mengzhao
Published: July 2024

e24121

Background: Although immune checkpoint inhibitors (ICIs) have improved survival of patients with malignancies, they also bring forth the immune-related adverse events (irAEs). Checkpoint inhibitor pneumonitis (CIP) stands out as a prominent complication following ICI therapy, while a substantial proportion of CIP cases present with severe manifestations, often leading to life-threatening outcomes. The management of severe and refractory CIP is challenging. This study was aimed to evaluate the efficacy and safety of ruxolitinib as an add-on therapy to corticosteroids for patients with severe CIP. Methods: In this investigator-initiated, multicenter, randomized, open-label, phase 2 trial, cancer patients with CTCAE grade (G) 3 or G4 CIP after ICIs therapy were enrolled. CIP patients were randomly assigned in a 1:1 ratio (randomized block method) to corticosteroids administration (the initial dosage was more than prednisone 1mg/kg/d or equivalent) or corticosteroids with add-on ruxolitinib administration (5mg twice a day for 2 weeks, followed by 5mg once a day for 2 weeks). The primary end point was the proportion of patients with a prednisone daily dosage of no more than 10mg and improvement to G1 CIP at week 8. Results: From April 2023 to Jan 2024, 19 patients were enrolled. There were 17 cases of G3 CIP and two cases of G4 CIP. Eleven cases were assigned to corticosteroids group (C group), and 8 cases were assigned to corticosteroids with add-on ruxolitinib administration group (R group). Fourteen patients completed 8 weeks of follow-up. Five cases (5/6, 83.3%) in the R group and three cases (3/8, 37.5%) in the C group improved to G1 CIP and received ≤prednisone 10mg daily at week 8. One patient in the R group and three cases in the C group failed to taper to 10mg/d prednisone or had G2-3 CIP. Two patients in the C group died from CIP. Two cases in R group and three cases in C group were still under follow-up. The G3 or higher treatment-related AEs (TRAEs) occurred in three patients, including one case of aspiration pneumonia in C group and two cases of COVID-19 (one in each group). Conclusions: Corticosteroids with add-on ruxolitinib administration could improve clinical responsiveness for severe CIP patients. The safety profile was controllable and favorable. Ruxolitinib could provide a valuable promising therapeutic option for cancer patients with severe CIP. Clinical trial information: NCT05899725 .
Positive baseline thyroid autoantibodies as a predictive biomarker for thyroid immune-related adverse events: A systematic review and meta-analysis.
Authors: Ponvilawan Ben , Wannaphut Chalothorn , Tselovalnikova Tatiana , Bansal Dhruv
Published: July 2024

e24124

Background: Thyroid dysfunction is one of the most common immune-related adverse events (irAE) by immune checkpoint inhibitors (ICI). Given the known relationship between antithyroid autoantibodies (ATA), including antithyroid peroxidase (TPO Ab) and anti-thyroglobulin (Tg Ab), and autoimmune thyroid disease, they could also play a role as a predictive biomarker for thyroid irAE (T-irAE). We performed this meta-analysis to evaluate the association of positive baseline thyroid autoantibodies and T-irAE. Methods: Eligible studies were screened using Ovid Medline and Embase databases with search terms related to ATA and thyroid irAE. Studies must be case-control or cohort studies with patients who received ICI and report the numbers of patients who have thyroid dysfunction and do not have thyroid dysfunction by the pre-ICI treatment statuses of ATA, TPO Ab, or Tg Ab. The pooled odds ratio (OR) and the associated 95% confidence interval (95% CI) were calculated using the Mantel-Haenszel method. Subgroup analysis by types of ICI (anti-PD1, anti-PD-L1, or combination treatment) and study region were also performed. The presence of publication bias was assessed by direct visualization of funnel plots. Results: After two rounds of screening, 19 case-control and five retrospective cohort studies were included in the meta-analysis. Patients who had positive baseline ATA had increased odds of developing T-irAE, hypothyroidism, and hyperthyroidism (pooled OR 10.95, 95% CI 6.65-18.02, I2= 38%; 6.82, 95% CI 2.99-15.56, I2= 27%; and 7.59, 95% CI 2.51-22.96, I2= 42%; respectively). Positive pre-treatment TPO Ab and Tg Ab were also independently associated with higher odds of hypothyroidism (pooled OR 5.01, 95% CI 2.87-8.75, I2= 4%, and 18.73, 95% CI 9.04-38.80, I2= 0%, respectively) and hyperthyroidism (pooled OR 2.94, 95% CI 1.57-5.52, I2= 25%, and 8.36, 95% CI 1.18-59.31, I2= 82%, respectively). The associations did not significantly differ between the types of ICI utilized and the study region. Visualization of funnel plots did not reveal a presence of publication bias. Conclusions: Pre-ICI treatment statuses of ATA, TPO Ab, and Tg Ab are associated with both hypothyroidism and hyperthyroidism. Thyroid autoantibodies as a baseline predictive tool can be helpful for early detection of T-irAE in patients who receive ICI therapy.
Screening for ocular toxicities of immunotherapy in a real-world population.
Authors: Barr Logan C. , Rullo Jacob , Baetz Tara D.
Published: July 2024

e24125

Background: Nivolumab, Pembrolizumab, and Ipilimumab have revolutionized the treatment of melanoma. However, patients receiving these treatments risk immunotherapy-related adverse events (IRAEs). IRAEs can occur in any organ system, are treated with steroids or immunosuppressive medications, and may require treatment delay or discontinuation. Ocular IRAEs, which are caused by off-target reactions with ocular immune mechanisms, are often identified after significant damage to the eye. Ocular IRAEs are rare in the literature with an approximate prevalence of 3.3%. After observing intraocular inflammation (uveitis) with uveal depigmentation (pigment release) in some patients receiving immunotherapy, we hypothesized that the rate of such events in a real-world population may be higher than previously reported. We predict ophthalmic screening and early intervention may prevent severe and potentially permanent ocular IRAEs. Methods: Patients starting immunotherapy for melanoma were referred to an ocular screening clinic at the Cancer Centre of Southeastern Ontario (Queen’s University, Kingston, Canada) for baseline ocular assessments. Repeat assessments occurred every three months (single agent) or at every cycle (dual immunotherapy). Intake visits included examination by an attending ophthalmologist, including examination for uveitis and anterior chamber free pigment under high-powered field. Intraocular inflammation (IOI) was defined as the presence of endothelial deposits and/or anterior chamber cell and/or pigment that was not present at baseline. Ocular findings were monitored alongside other IRAEs during treatment. Results: 28 patients (17 male, 11 female) receiving adjuvant (46.4%) or palliative (53.6%) immunotherapy for melanoma were evaluated. 9 of these patients received dual immunotherapy (Ipilimumab/Nivolumab) and 19 received single agent immunotherapy. IOI was identified in 11 patients (39.2%), while only 4 presented with symptoms. None of the patients had overt signs of anterior segment inflammation such as erythema, conjunctival injection, and chemosis. IOI developed in 54.5% of dual immunotherapy-treated patients. Patients with ocular IRAEs were treated with topical/systemic steroids or other immunosuppressive medications. None required discontinuation of immunotherapy. The development of IOI was more common in metastatic patients whose cancer was responding to immunotherapy, and many of these patients sustained IRAEs in other organ systems. Conclusions: Our findings suggest IOI related to ocular IRAEs are quite common and develop in a third of patients receiving immunotherapy for melanoma. Ocular screening for IOI identified early, often asymptomatic toxicities that could progress to permanent visual disability. Further evaluation of dedicated ocular screening is indicated in patients receiving immunotherapy.
Immune-related adverse events associated with nivolumab: Analysis of the FAERS database in the United States.
Authors: Liu Yi , 朱 亚宁
Published: July 2024

e24126

Background: To describe the risk of nivolumab adverse events (AEs) and to provide a reference for the safe clinical to use this drug. Methods: Nivolumab AE reports from January 2014 to December 2023 were collected from the FDA Adverse Event Reporting System, with a total of 133,12811 background patients (3,853,1848 occurrences of adverse events) included in the analysis, of which the number of patients in the target drug population was 60,625 (16,512 occurrences of adverse events). The number of patients in the target drug population was 60625 (161512 adverse events). Signals were detected using the Reporting Odds Ratio (ROR) method in conjunction with the Proportional Reporting Ratio (PRR), with signal judgment thresholds typically using a ≥ 3, and the lower limit of the 95% confidence interval for the ROR being greater than 1, The ROR and PRR (using a ≥ 3, and the lower limit of the 95% confidence interval for the ROR being greater than 1) were compared to the PRR. When ROR and PRR (using a ≥ 3, PRR ≥ 2 and chi-square ≥ 4 as thresholds) were used in combination, signal crossover between the two methods was defined as a positive risk signal. The preferred system organ classification (SOC) and preferred terminology (PT) of the current version of the MedDRA dictionary were used to classify AEs, and the top 30 PTs in terms of AE signal intensity were selected for analysis. Results: A total of 161,512 reports of AE with nivolumab as the first suspected drug were collected, involving 5174 PTs. A total of 995 positive PT signals were calculated using the combined ROR and PRR assay. The top 5 risk signals induced by nivolumab were immune-mediated small bowel colitis (ROR (95% CI) 114.42 (103.26-126.79), PRR (Chi-Square) 114.04 (40959.8)), pituitary gland inflammation (ROR (95% CI) PRR (Chi-Square) 88.60 ( 79.17-99.15)PRR(Chi-Square)88.37(26256.6)), fulminant type 1 diabetes mellitus (ROR(95% CI)213.73(183.24-249.30),PRR(Chi-Square)213.33(34295.5)) immune-mediated pneumonias (ROR(95% CI) 114.08 (99.42-130.89),PRR(Chi-Square) 113.87 (22764.4)), immune-mediated hepatitis (ROR(95% CI) 86.09 (75.08-98.71),PRR(Chi-Square) 85.94 (17262.8)).The top 5 SOCs were systemic diseases and various reactions at the site of administration in 25447 cases (15.76%), gastrointestinal disorders in 25447 cases(15.76%), gastrointestinal disorders 16,282 cases (10.08%), various types of injuries, poisoning and operational complications 12,510 cases (7.57%), respiratory, thoracic and mediastinal disorders 11,572 cases (7.16%), as well as benign, malignant, and tumors of undetermined nature (including cystic and polypoid) 10,486 cases (6.49%). Conclusions: The risk signal of autoimmune diseases caused by nivolumab is relatively strong, and it is recommended that clinicians should pay attention to the possible autoimmune diseases of various systems during the use of the drug.
Metabolic changes due to dexamethasone premedication in patients with breast cancer.
Authors: Scontre Vanessa Armenio , Lapate Milena Degaspari Gonzales , Testa Laura , Watarai Gabriel , Estevez-Diz Maria Del Pilar
Published: July 2024

e24127

Background: The treatment for patients diagnosed with breast cancer is based, in the curative intent scenario, on chemotherapy (CT) such as anthracyclines and taxanes. We are aware that some drugs are widely used and necessary before CT administration to avoid unwanted side effects. Dexamethasone is part of the arsenal of these medications, however, pathological conditions resulting from high doses of administration of this corticosteroid are clinically evident in these patients. In this study we aim to evaluate whether omitting a dose of corticosteroid therapy as a premedication after the second week of treatment with taxane can prevent or reduce the incidence of metabolic changes, and its impact on a patient's quality of life (QoL). Methods: A prospective, randomized, open label study. Breast cancer patients with indication for adjuvant or neoadjuvant treatment with doxorubicin, cyclophosphamide and paclitaxel + trastuzumab (AC-T+ TTZ) chemotherapy were randomized to standard arm, with dexamethasone 10 mg IV administered pre-paclitaxel in all cycles and experimental arm, where dexamethasone was omitted from the premedication from the third to the last taxane application. Results: 86 patients were included, 43 patients in each arm. Premedication was administered every cycle and/ or week before the administration of chemotherapy drugs. Patients had lab analysis and QoL EORTC QLQ-C30 before the beginning of the CT, before the third application of Paclitaxel and 24 hours after the last administration. We observed an increase in ACTH in the experimental group, which is predictable since high doses of corticosteroids suppress the hormone pathway; a drop of insulin levels in its levels in the experimental group and stability in its serum levels in the control group; a stability of GH and IGF-1 in the control group and a more pronounced drop in circulating levels of this hormone in the experimental group. The control group had a greater increase in the excretion of aldosterone, probably due water retention caused by the use of dexamethasone. There were no adverse events reported in the experimental group and also hypersensitivity or anaphylactic reactions were not observed. The EORTC-QLQ-C30 scores related to diarrhea, constipation, inappetence and insomnia were better in the experimental group, as well the average score for global health. Conclusions: The omission of dexamethasone in patients in the experimental group improved QOL scores related to common AEs during CT, mainly GI and also insomnia. Insulin levels were also lower in this group. The potential reduction of the incidence of metabolic syndrome seems palusible but would require larger sample size. The short term safety and tolerability of this regimen warrants its use in larger populations. Clinical trial information: NCT04350229 .
A phase 2, open-label, single-arm, prospective, multicenter study of nab-sirolimus plus letrozole in advanced or recurrent endometrioid endometrial cancer.
Authors: Dockery Lauren E. , Slomovitz Brian M. , Musa Fernanda , Mathews Cara Amanda , Priebe Anna M. , Green Angela , Puechl Allison , Birrer Michael J. , Spirtos Nicola M. , Ding Li , Schmid Anita N. , Navarro Willis H. , Moore Kathleen N.
Published: July 2024

TPS5640

Background: This clinical trial is designed to evaluate the antitumor activity of nab-sirolimus in combination with letrozole in patients with advanced or recurrent endometrioid endometrial carcinoma (EEC). Despite recent pivotal data demonstrating improved outcomes with immunotherapy plus chemotherapy, regardless of mismatch repair status, alternative nonchemotherapy-based treatment options for patients with advanced or recurrent EEC remain necessary. Dysregulation of mTOR signaling is implicated in the pathology of EEC, in which >80% harbor PTEN or PI3K/Akt/mTOR pathway alterations. Moreover, crosstalk between mTOR and estrogen receptor signaling pathways is associated with endocrine therapy resistance. GOG-3007 and other phase 2 studies have demonstrated that the combination of conventional mTOR inhibitors (mTORis) and endocrine therapy provides clinical benefit in patients with EEC. nab-Sirolimus is an mTOR inhibitor that uses albumin-bound sirolimus nanoparticles given by IV and is approved by the US FDA for malignant perivascular epithelioid cell tumor. Preclinical data of nab-sirolimus demonstrated improved tumor accumulation, mTOR inhibition, and tumor growth suppression compared with conventional mTORis. We hypothesize that the simultaneous inhibition of mTOR and ER with nab-sirolimus and letrozole, respectively, may provide a signal of synergistic antitumor activity in patients with recurrent EEC. Methods: In this phase 2, open-label, single-arm, multicenter study (NCT05997017), nab-sirolimus (100 mg/m2, intravenous, on days 1 and 8 of each 21-day cycle) and letrozole (2.5 mg, oral, daily) are administered to patients (~29 planned, Simon’s 2-stage design) with clinically confirmed, advanced, or recurrent EEC. Eligibility criteria include age ≥18 years, ≤1 prior chemotherapy-based regimen in the advanced, metastatic, or recurrent setting, prior adjuvant chemotherapy is permitted, Eastern Cooperative Oncology Group performance status score 0 or 1, naive to mTORi, and measurable disease (per Response Evaluation Criteria in Solid Tumors [RECIST] v1.1). The primary endpoint is best overall response rate by RECIST v1.1. Key secondary endpoints include duration of response, disease control rate (defined as complete response plus partial response plus stable disease of ≥12 weeks after start of treatment), progression-free survival, overall survival, and safety. Exploratory endpoints include correlation of baseline molecular biomarkers with clinical outcomes. The trial is open for enrollment. Clinical trial information: NCT05997017 .
PEMDA-HN, an open-label, phase II, randomized controlled study of danvatirsen plus pembrolizumab compared to pembrolizumab alone in first-line recurrent and/or metastatic head and neck squamous cell carcinoma (RM HNSCC).
Authors: Posner Marshall R. , Wong Deborah J.L. , Harrington Kevin Joseph , O'Neal Richard Lee , Makris Lukas , Perdomini Morgane , MacIntyre Susan , Denker Andrew , Saba Nabil F.
Published: July 2024

TPS6113

Background: Signal transducer and activator of transcription 3 (STAT3) plays critical roles in promotion of an immune-suppressive tumor microenvironment and survival of tumor cells. Danvatirsen (DANVA) is a 16-nucleotide, generation 2.5 antisense oligonucleotide designed to down-regulate the expression of human STAT3 mRNA. Over 500 patients with hematologic malignancies or solid tumors have been exposed to DANVA monotherapy or in combination. A tolerable safety profile has been demonstrated for DANVA and toxicities are manageable. The SCORES study in recurrent and/or metastatic (RM) HNSCC patients, naïve to programmed cell death (ligand)1 (PD-(L)1) therapy, demonstrated that DANVA in combination with the PD-L1 inhibitory antibody durvalumab administered in the second line setting appeared to result in a higher objective response rate (ORR) (22.6% [12.3-36.2]) compared with the ORRs seen with durvalumab alone in prior studies (Cohen E. et al. Ann. Oncol., 2018). Several patients had complete responses (CR, 9.4%). The ORR was higher in patients with a PD-L1 tumor proportion score (TPS) ≥1 and ≥20, with increasing benefit noted with higher PD-L1 expression compared with historic anti-PD-(L)1 monotherapy data. The current study aims at evaluating the first-line combination of DANVA with pembrolizumab, an anti-PD-1 agent approved as first-line monotherapy for RM HNSCC in patients with PD-L1 positive disease. Methods: PEMDA-HN is a multicenter, open-label, randomized phase 2 study utilizing a Bayesian Optimal design (BOP2). Approximatively 81 RM HNSCC patients with a PD-L1 combined positive score (CPS) score ≥1 will be randomized in a 2:1 ratio stratified based on CPS<20 and CPS≥20 to receive either DANVA (3 mg/kg IV Days 1, 3, and 5 and then weekly starting on Day 8) and pembrolizumab (200 mg IV every 3 weeks) or pembrolizumab alone as a first line therapy for recurrent or metastatic disease. Eligible patients will receive study treatment until disease progression or discontinuation. The primary endpoint of the study is ORR by response evaluation criteria in solid tumors version 1.1 (RECIST 1.1) as assessed by the investigator. Key secondary objectives are safety, additional antitumor activity evaluation (CR rate, duration of response, disease control rate, progression-free and overall survival) and pharmacokinetics. Efficacy (e.g. ORR, CR rate) will be evaluated in all patients and in subsets of patients with CPS<20, CPS≥20 and CPS≥50. Exploratory endpoints include but are not limited to target engagement and biomarker evaluation. The study is being, or will be, conducted at US, South Korea and United-Kingdom study centers. Clinical trial information: NCT05814666 .
The Problems of Human Embryos Genome Editing from the Position of Islam Denominations
Authors: Minchenko Tatiana , Gribkov Edward
Published: July 2024

Biomedical technology is one of the most relevant and rapidly developing branches of science. In response to the major problems of bioethics and bio-law, bioethical dilemmas emerge in society, which constrain the abuse of new technologies. Medical discoveries, on the one hand, can greatly facilitate the life of humankind, but, on the other hand, the problem of interference in human nature actualizes the most fundamental questions concerning its ontology, the boundaries of permissible transformations, the responsibility of a scientist and a specialist, applying the latest technologies, for remote and unpredictable consequences, due to the integrity and interconnectedness of various aspects of human nature. This paper presents the experience of generalizing the attitude of the main Islamic confessions and different approaches in the legislation of Islamic countries to the problem of editing the human embryo genome. Based on a review of scientific and religious literature, it is concluded that, although the Islamic world is increasingly using Western models of behavior, in matters of the permissibility of editing the human embryo genome from the point of view of Islamic bioethics, it is necessary to rely on the principles of Sharia and multidisciplinary knowledge.
Nietzsche’s Intellectual Integrity and Metaphysical Comfort
Authors: Ojimba Anthony Chimankpam
Published: July 2024

This paper examines Nietzsche’s intellectual integrity, with a view to showing that despite his attempt to overcome metaphysics, using this concept, Nietzsche remains within the comfort of metaphysics. Intellectual integrity represents Nietzsche’s unique style of questioning and his critical method of analysing Western metaphysical foundations. It is a flexible and dialectic principle, which approaches the question of ‘being’ as a dynamic process of endless interpretations and becoming, instead of as a fixed essence or a metaphysical absolute. Attempts are made, in the paper, to examine the dynamics of Nietzsche’s intellectual integrity, as well as its intimate link with other key concepts in his philosophy. To achieve its goal, the paper adopts the method of historical hermeneutics and textual analysis.
Europa Środkowa, Środkowo-Wschodnia czy zapomniana? Uwagi o historii idei na emigracji i w kraju
Authors: Łukasiewicz Sławomir
Published: July 2024

Punktem wyjścia artykułu jest historiograficzna i polityczna dyskusja wokół koncepcji Europy Środkowo-Wschodniej rozpoczęta przez Oskara Haleckiego na emigracji. Jego zdaniem Rosja nie była państwem europejskim. Po upadku Związku Radzieckiego w latach dziewięćdziesiątych koncepcja Haleckiego została przyjęta w Polsce, czego jednym z przejawów było utworzenie Instytutu Europy Środkowo-Wschodniej pod kierownictwem Jerzego Kłoczowskiego. W ostatniej dekadzie koncepcja ta została zastąpiona przez ideę współpracy Trójmorza (nawiązującą do międzywojennych koncepcji Intermarium) i pojęcie Europy Środkowej. Po totalnej agresji Rosji na Ukrainę dyskusja na temat podziałów Europy, w tym koncepcji Europy Środkowo-Wschodniej, wydaje się nieunikniona.
Polsko-ukraińskie rozmowy gospodarcze wiosną i latem 1920 r. Dlaczego nie doszło do porozumienia?
Authors: Pisuliński Jan
Published: July 2024

Celem artykułu jest przedstawienie okoliczności i przebiegu polsko-ukraińskich negocjacji gospodarczych prowadzonych od 8 V do 2 VIII 1920 r. Zakończyły się one niepowodzeniem, gdyż strona ukraińska przewlekała rozmowy, nie chcąc przystać na polskie żądania koncesji gospodarczych w Zagłębiu Krzyworoskim.
Między nauką i polityką: interpretacja przeszłości w książce Paula Roberta Magocsiego „Pod osłoną gór. Dzieje Rusi Karpackiej i Karpatorusinów”
Authors: Syrnyk Jarosław
Published: July 2024

Artykuł recenzyjny odpowiada na pytanie, z jakiego rodzaju interpretacją przeszłości mamy do czynienia w pracy Paula Roberta Magocsiego Pod osłoną gór. Dzieje Rusi Karpackiej i Karpatorusinów. Tekst koncentruje się na znaczeniach wydobywanych i nadawanych im przez autora, odnosi się do jej podstaw teoretycznych – kategorii narodu i geografii uzupełnionych kategoriami statystyki demograficznej i języka. Przeprowadzona analiza prowadzi do wniosku, że spójność i perswazyjność wywodu pracy stała się w niej elementem dominującym. Między innymi dlatego otrzymujemy tam etnonim Karpatorusini, pośrednio wydobyty z nazwy terytorium Ruś Karpacka zasiedlanego przez wspólnotę, która wyznacza jego granice.
Zapomniany sługa władzy – Marcin z Szadka, dyplomata i doradca
Authors: Korczak Lidia
Published: July 2024

W czasie krótkiego pobytu na Litwie (1434–1445) skromnemu duchownemu z Polski udało się dostać do bliskiego otoczenia wielkiego księcia i stać się jego nieformalnym doradcą. Jest to przykład nietypowej kariery człowieka „znikąd”, pozostającego w cieniu dostojników kościelnych i świeckich, a przy tym odgrywającego istotną rolę w ważnych politycznie wydarzeniach. Marcin z Szadka wyszedł z niebytu, by od razu sięgnąć po wysoką kościelną godność (archidiakonat wileński w 1435 r.), a w chwili politycznego przesilenia w polsko-litewskich stosunkach uratować unię, przekonując wielkiego księcia i panów litewskich do połączenia w jednym ręku polskiej korony i wielkoksiążęcej mitry (bezkrólewie w Polsce i negocjacje w sprawie elekcji w latach 1445–1446). Był jedną z tych osób publicznych w Wielkim Księstwie Litewskim połowy XV wieku, która konsekwentnie wspierała unię i dzięki osobistym znajomościom łączyła intelektualne środowisko katedralne Wilna i Krakowa. Po wypełnieniu ważnej dyplomatycznej misji w Inflantach (1445 r.) Marcin z Szadka zniknął z pola źródłowego widzenia.