UGT1A1 Testing in Breast Cancer: should it become routine practice in patients treated with antibody-drug conjugates?

The use of genetic testing to personalize therapeutic strategies in cancer is rapidly evolving and thus changing the landscape of treatment of oncologic patients. The UGT1A1 gene is an important component for the metabolism and glucoronidation of certain drugs, including irinotecan and sacituzumab govitecan (SG); therefore, various UGT1A1 polymorphisms leading to decreased function of the UGT1A1 enzyme may lead to increased risk of treatment-related side effects. Testing for UGT1A1 polymorphism is not routinely adopted in clinical practice; that is due to the lack of concise studies and recommendations concerning the clinical relevance of this test and its impact on the quality of life of cancer patients. The knowledge regarding UGT1A1 polymorphism and its clinical relevance will be reviewed in this article, as well as the published literature on the association between UGT1A1 polymorphism and the toxicity risk of irinotecan as well as sacituzumab govitecan. The current recommendations and guidelines on UGT1A1 testing will be discussed in detail in the hopes of providing guidance to oncologists in their clinical practice.

A Comprehensive Review on the Role of Lurbinectedin in Soft Tissue Sarcomas.

OPINION STATEMENT: Soft tissue sarcoma (STS), a substantial group of aggressive and rare tumors with tissue heterogeneity, is infrequently represented in clinical trials with an urgent necessity for newer treatment options. Lurbinectedin, an analog of trabectedin, is currently approved, in various countries, as a single agent, for the treatment of patients with relapsed small cell lung cancer (SCLC). However, preclinical and phase I and phase II trials have demonstrated the efficacy of lurbinectedin in different tumor types, including STS. The better understanding of the pathophysiology and evolution of STS as well as the mechanism of action of lurbinectedin in addition to the available data regarding the activity of this drug in this subset of patients will pave the way to newer therapeutic options and strategies.

Desmoid-type fibromatosis: Current therapeutic strategies and future perspectives.

Desmoid tumors (DT) are rare, slow-growing, locally invasive soft tissue tumors that often pose significant therapeutic challenges. Traditional management strategies including active surveillance, surgery, radiotherapy, and systemic therapy which are associated with varying recurrence rates and high morbidity. Given the challenging nature of DT and the modest outcomes associated with current treatment strategies, there has been a growing interest in the field of γ-secretase inhibitors as a result of its action on the Wnt/ß-catenin signaling pathway. In this review article, we will shed the light on the pathogenesis and molecular biology of DT, discuss its symptoms and diagnosis, and provide a comprehensive review of the traditional therapeutic approaches. We will also delve into the mechanisms of action of γ-secretase inhibitors, its efficacy, and the existing preclinical and clinical data available to date on the use of these agents, as well as the potential challenges and future prospects in the treatment landscape of these tumors.

Insights of Medical Students and Graduates Toward Electronic Learning During the COVID-19 Pandemic in Lebanon: A National Cross-Sectional Study.

OBJECTIVE: This study examines the perceptions of Lebanese medical students and graduates regarding the switch to electronic learning (e-learning) and measures their psychological distress amid the COVID-19 pandemic, compounded by an unprecedented financial collapse and the August 4 Beirut blast. METHODS: This is a national cross-sectional descriptive study, consisting of a 48-item questionnaire, diffused online to Lebanese medical students between February 8 and 21, 2021. The survey divided into 5 sections assesses for (1) Sociodemographic information, (2) implemented changes in medical education delivery precipitated by the pandemic, (3) students' perceptions regarding the effectiveness, advantages, and barriers of e-learning, and (4) role of e-learning in clinical training. Finally, students' psychological distress was measured, using the Kessler 10-item distress scale (K10). Descriptive analyses were performed using Stata version 13 and Excel. RESULTS: 1060 responses were recorded (27% response rate) across all Lebanese medical schools. Although 71.6% of participants found e-learning to be stimulating, half of the participants thought it was not equally effective to face-to-face learning. Around 73.1% of students felt they were not able to learn hands-on clinical skills. Lebanese students identified cost savings (food, transportation etc) and poor internet connectivity are the most common advantage and barrier, respectively; 77.8% of participants showed high/very high levels of distress (K10 score ≥22). CONCLUSIONS: Ensuring accessibility and availability of resources such as electricity and internet is of utmost priority. Lebanese medical schools need to incorporate clinical training experiences to their virtual platforms to maintain the quality of medical education to their students. A particular attention to students' mental health is warranted, by increasing awareness and access to mental health services.

LAG-3 Inhibitors: Novel Immune Checkpoint Inhibitors Changing the Landscape of Immunotherapy.

One of the most important steps forward in the management of cancer was the discovery of immunotherapy. It has become an essential pillar in the treatment paradigm of cancer patients. Unfortunately, despite the various options presented with immune checkpoint inhibitors (ICIs), the benefit is still limited to select patients and the vast majority of these patients gain either minimal benefit or eventually progress, leaving an unmet need for the development of novel therapeutic agents and strategies. Lymphocyte activation gene-3 (LAG-3), an immune checkpoint receptor protein, is a molecule found on the surface of activated T-cells. It plays a major role in negatively regulating T-cell function thereby providing tumors with an immune escape in the tumor microenvironment (TME). Given its importance in regulating the immune system, LAG-3 has been considered as a promising target in oncology and precision medicine. To date, two LAG-3-directed agents (eftilagimod alpha and relatlimab) have been approved in combination with programmed death-1 (PD-1) inhibitors in the setting of advanced solid tumors. In this review, we discuss the structure of LAG-3, its mechanism of action, and its interaction with its ligands. We also shed light on the emerging treatments targeting LAG-3 for the treatment of solid tumors.

Mechanisms of Resistance to Antibody-Drug Conjugates.

The treatment of cancer patients has dramatically changed over the past decades with the advent of monoclonal antibodies, immune-checkpoint inhibitors, bispecific antibodies, and innovative T-cell therapy. Antibody-drug conjugates (ADCs) have also revolutionized the treatment of cancer. Several ADCs have already been approved in hematology and clinical oncology, such as trastuzumab emtansine (T-DM1), trastuzumab deruxtecan (T-DXd), and sacituzumab govitecan (SG) for the treatment of metastatic breast cancer, and enfortumab vedotin (EV) for the treatment of urothelial carcinoma. The efficacy of ADCs is limited by the emergence of resistance due to different mechanisms, such as antigen-related resistance, failure of internalization, impaired lysosomal function, and other mechanisms. In this review, we summarize the clinical data that contributed to the approval of T-DM1, T-DXd, SG, and EV. We also discuss the different mechanisms of resistance to ADCs, as well as the ways to overcome this resistance, such as bispecific ADCs and the combination of ADCs with immune-checkpoint inhibitors or tyrosine-kinase inhibitors.

Overview of the role of liquid biopsy in cancer management.

With the emergence of novel targeted therapeutic options in early-stage and advanced-stage malignancies, researchers have shifted their focus on developing personalized treatment plans through molecular profiling. Circulating tumor DNA (ctDNA) is a cell-free DNA (ctDNA) fragment, originating from tumor cells, and circulating in the bloodstream as well as biological fluids. Over the past decade, many techniques were developed for liquid biopsies through next-generation sequencing. This alternative non-invasive biopsy offers several advantages in various types of tumors over traditional tissue biopsy. The process of liquid biopsy is considered minimally invasive and therefore easily repeatable when needed, providing a more dynamic analysis of the tumor cells. Moreover, it has an advantage in patients with tumors that are not candidates for tissue sampling. Besides, it offers a deeper understanding of tumor burden as well as treatment response, thereby enhancing the detection of minimal residual disease and therapeutic guidance for personalized medicine. Despite its many advantages, ctDNA and liquid biopsy do have some limitations. This paper discusses the basis of ctDNA and the current data available on the subject, as well as its clinical utility. We also reflect on the limitations of using ctDNA in addition to its future perspectives in clinical oncology and precision medicine.

Letter and Category Fluency: Normative Data for Lebanese Older Adults.

BACKGROUND: Verbal fluency tasks are frequently used for neuropsychological assessment in clinical practice and research. It consists of two tasks namely category and letter fluency tests. OBJECTIVE: To determine normative values in category (animals, vegetables, fruits) and letter fluency [Mim () "M", Alif () "A", Baa () "B"] tasks in Arabic language in 60 s. METHODS: This study was a cross-sectional national survey and included 859 community-dwelling, cognitively intact Lebanese residents aged ≥55 years. Norms were presented according to age (55-64 years, 65-74 years, ≥75 years), sex and level of education (illiterate, no diploma, primary certificate, baccalaureate or higher). RESULTS: Level of education had the most significant positive effect on verbal fluency tasks performance amongst Lebanese older adults. The negative effect of older age was more prominent in the category fluency task compared to the letter fluency task. Women outperformed men in vegetables and fruits categories. CONCLUSION: This study provides clinicians with normative scores of category and letter fluency tests, which can be used for neuropsychological assessment of older Lebanese patients being evaluated for cognitive disorders.

Anxiety, depression and post-traumatic stress disorder in patients on hemodialysis in the setting of the pandemic, inflation, and the Beirut blast: a cross-sectional study.

BACKGROUND: In 2020, Lebanon has witnessed its worst economic crisis, exacerbated by the COVID-19 pandemic and a massive explosion of its capital. Amidst these stressors, this study aims at assessing the prevalence of depression, anxiety, suicidality, post-traumatic stress disorder (PTSD) and cognitive impairment in patients undergoing hemodialysis in an academic hospital destroyed by the explosion. METHODS: This cross-sectional study conducted 6 months after the blast included adults on hemodialysis, with no previous diagnoses of dementia or intellectual disability. It explores prevalence rates of psychiatric disorders, in addition to other medical and psychosocial variables such as frailty, malnutrition, sarcopenia, quality of life and religiosity. RESULTS: Forty two patients (mean age 66.1; SD: 11.2 years) undergoing hemodialysis for 6.12 years (SD:7.22 years) were included. Anxiety and depression rates reached 54.8% and 57.1% using cut-offs of 6 and 7 respectively on the Hospital Anxiety and Depression rating Scale. 9.5% of the patients reported being in the hospital at the time of the blast and 7.1% reported being injured. 33.3% screened positively for PTSD using a cut-off of 23 on the PCL-5. 26.2% had passive death wishes and 7.1% had suicide plans, however no one had attempted it. 23.8% were found cognitively impaired as shown by the Mini-Cog (<3). Around two-third of participants were moderately to severely malnourished per the GLIM criteria. One third suffered from frailty, according to the FRAIL screening tool. Around 60% suffered from sarcopenia, based on handgrip strength measures. These findings contrast with "acceptable to good" quality of life subjectively reported by participants on the Short Form 36 (SF-36) Health Survey. While one-third of participants participated in organizational religious activities, 88% reported significant subjective meaning of religion in their heart. CONCLUSIONS: Rates of depression, anxiety, PTSD, suicidality, and cognitive impairment were found to be alarming in the setting of an urban dialysis unit following a major explosion. Psychiatric disorders were found to be compounded with increased prevalence of malnutrition, frailty, and sarcopenia. These findings urge healthcare providers to implement early diagnostic and intervention strategies to improve both mental and physical wellbeing of this vulnerable population, in similar settings.

CD4 CAR-T cells targeting CD19 play a key role in exacerbating cytokine release syndrome, while maintaining long-term responses.

BACKGROUND: To date, T cells redirected with CD19-specific chimeric antigen receptors (CAR) have gained impressive success in B-cell malignancies. However, treatment failures are common and the occurrence of severe toxicities, such as cytokine release syndrome (CRS), still limits the full exploitation of this approach. Therefore, the development of cell products with improved therapeutic indexes is highly demanded. METHODS: In this project, we investigated how CD4 and CD8 populations cooperate during CD19 CAR-T cell responses and what is their specific role in CRS development. To this aim, we took advantage of immunodeficient mice reconstituted with a human immune system (HuSGM3) and engrafted with the B-cell acute lymphoblastic leukemia cell line NALM-6, a model that allows to thoroughly study efficacy and toxicity profiles of CD19 CAR-T cell products. RESULTS: CD4 CAR-T cells showed superior proliferation and activation potential, which translated into stronger stimulation of myeloid cells, the main triggers of adverse events. Accordingly, toxicity assessment in HuSGM3 mice identified CD4 CAR-T cells as key contributors to CRS development, revealing a safer profile when they harbor CARs embedded with 4-1BB, rather than CD28. By comparing differentially co-stimulated CD4:CD8 1:1 CAR-T cell formulations, we observed that CD4 cells shape the overall expansion kinetics of the infused product and are crucial for maintaining long-term responses. Interestingly, the combination of CD4.BBz with CD8.28z CAR-T cells resulted in the lowest toxicity, without impacting antitumor efficacy. CONCLUSIONS: Taken together, these data point out that the rational design of improved adoptive T-cell therapies should consider the biological features of CD4 CAR-T cells, which emerged as crucial for maintaining long-term responses but also endowed by a higher toxic potential.

An adapted Arabic version of the Test of Nine Images for the illiterate Lebanese population: Validation and preliminary normative data.

OBJECTIVES: In the absence of a simple validated instrument to screen for cognitive impairment among illiterate Lebanese older adults, the aims of this study were to validate an Arabic version of the Test of Nine Images (A-TNI93) adapted by the Working Group on Dementia at Saint Joseph University: Groupe de Travail sur les Démences de l'Univesité Saint Joseph (GTD-USJ) for illiterate older Lebanese and to establish normative data. METHOD: A national population-based sample of 332 community-dwelling illiterate Lebanese aged 55 years and older was administered the A-TNI93 (GTD-USJ) scoring free and overall recall. The sample is part of a larger national sample (1342 participants) used to validate an Arabic version of the Mini-Mental State Examination already reported. Reproducibility, sensitivity, specificity, and area under the curve of the A-TNI93 (GTD-USJ) scoring to detect cognitive impairment according to Clinical Dementia Rating (CDR) as the gold standard were measured. Normative data were established among 188 cognitively normal participants. RESULTS: A threshold score of six on free recall (FR) provided a sensitivity of 66.7% and a specificity of 90.5%. The area under the curve was 0.93. By taking either scores, that is, a FR ≤ 6 or a total recall ≤ 8, the A-TNI93 (GTD-USJ) slightly improved dementia case detection with a sensitivity of 70.8% and a specificity of 88%. Normative data illustrate the distribution of cognitive performance among illiterate older adults. CONCLUSIONS: Compared to the CDR requiring physician's competence, the A-TNI93 (GTD-USJ) is a valid Arabic adaptation to screen for cognitive impairment among illiterate Lebanese older adults.

Psychometric properties of the 37-item Functional Assessment of Cancer Therapy-Cognitive Function (FACT-Cog) scale.

Aim: To validate the French version of the 37-item Functional Assessment of Cancer Therapy-Cognitive Function, including the four items related to multitasking, previously excluded from the scoring algorithm. Materials & methods: A cross-sectional study was carried out among 261 cancer patients. Validity was confirmed by factor analyses using the principal component analysis technique. Results: Construct validity was demonstrated, and items loaded on subscales with adequate sample adequacy to factor analyses outcomes. Better cognitive functioning was noted with age and in working patients, whereas lower functioning was observed in metastatic patients. Conclusion: The 37-item French tool is valid and reliable; questions related to multitasking could be included in the score.

A study was carried out among 261 cancer patients to evaluate their cognitive function using the French version of a 37-item validated scale. Our results demonstrated that the tool is valid and reliable. Better cognition was noted in older patients compared with younger ones, and lower cognitive functioning was observed in patients with metastatic cancer. This newly validated tool could help clinicians assess cognition in their routine practice.

Clinical and genetic factors associated with self-reported cognitive deficits in women with breast cancer: the "CAGE-Cog" study.

BACKGROUND: Breast cancer patients undergoing chemotherapy treatment are at particular risk of experiencing acute cognitive impairment leading to daily challenges in decision-making and reduced quality of life and functional autonomy. The aim was to assess the relationship between clinical and genetic factors and cognitive function in a sample of patients with breast cancer undergoing chemotherapy. METHODS: A cross-sectional study was carried out between November 2017 and June 2019 on women (N = 112) treated for breast cancer by intravenous chemotherapy at the oncology outpatient unit of Hôtel-Dieu de France Hospital, Beirut. Patients were evaluated with the 37-item Functional Assessment of Cancer Therapy-Cognitive Function (FACT-Cog). Other validated scales were also used to assess depression, anxiety, sleep disorders, pain, and fatigue. DNA was obtained by a buccal swab (FTA®technology) for genotyping of different genes (ABCB1, COMT, DRD2, OPRM1, CLOCK, CRY2, and PER2) using the Lightcycler®(Roche). RESULTS: The mean age of participants was 56.04 years. Multivariable analysis, taking the four FACT-Cog subscores as the dependent variables, showed that the mean cognitive score decreased with higher depression, anxiety, and insomnia scores. Patients with university education levels had better perceived cognitive abilities than those with primary education. Moreover, carrying the G allele for the OPRM1 polymorphism (c.118A > G;rs197791) was significantly associated with a better cognitive function compared to AA patients (B = 2.05; p = 0.038). CONCLUSIONS: A comprehensive oncological care plan should include a personalized assessment of all factors related to cognitive functioning in cancer patients, particularly anxiety and depression, to achieve an optimal patient outcome.