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.

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.

Protein Phosphatase 4 Negatively Regulates the Immune Deficiency-NF-κB Pathway during the Drosophila Immune Response.

The evolutionarily conserved immune deficiency (IMD) signaling pathway shields Drosophila against bacterial infections. It regulates the expression of antimicrobial peptides encoding genes through the activation of the NF-κB transcription factor Relish. Tight regulation of the signaling cascade ensures a balanced immune response, which is otherwise highly harmful. Several phosphorylation events mediate intracellular progression of the IMD pathway. However, signal termination by dephosphorylation remains largely elusive. Here, we identify the highly conserved protein phosphatase 4 (PP4) complex as a bona fide negative regulator of the IMD pathway. RNA interference-mediated gene silencing of PP4-19c, PP4R2, and Falafel, which encode the catalytic and regulatory subunits of the phosphatase complex, respectively, caused a marked upregulation of bacterial-induced antimicrobial peptide gene expression in both Drosophila melanogaster S2 cells and adult flies. Deregulated IMD signaling is associated with reduced lifespan of PP4-deficient flies in the absence of any infection. In contrast, flies overexpressing this phosphatase are highly sensitive to bacterial infections. Altogether, our results highlight an evolutionarily conserved function of PP4c in the regulation of NF-κB signaling from Drosophila to mammals.

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.

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.

Fatigue in breast cancer patients on chemotherapy: a cross-sectional study exploring clinical, biological, and genetic factors.

BACKGROUND: Cancer-related fatigue (CRF) is one of the most common and distressing complaints reported by cancer patients during chemotherapy considerably impacting all aspects of a patient's life (physical, psychosocial, professional, and socioeconomic). The aim of this study was to assess the severity of cancer-related fatigue in a group of breast cancer patients undergoing chemotherapy and explore the association between fatigue scores and sociodemographic, clinical, biological, psychiatric, and genetic factors. METHODS: A cross-sectional pilot study carried out at the oncology outpatient unit of Hôtel-Dieu de France University Hospital recruited 67 breast cancer patients undergoing chemotherapy between November 2017 and June 2019 to evaluate fatigue using the EORTC QLQ-C30 scale (European Organization for the Research and Treatment of Cancer Quality of Life Questionnaire). Genotyping for seven gene polymorphisms (COMT, DRD2, OPRM1, CLOCK, PER2, CRY2, ABCB1) was performed using the Lightcycler® (Roche). RESULTS: The prevalence of fatigue was 46.3%. Multivariable analysis taking the fatigue score as the dependent variable showed that a higher number of cycles and a lower hemoglobin level were significantly associated with higher odds of exhibiting fatigue. Moreover, having at least one C allele for DRD2 SNP (vs. TT) was significantly associated with a 4.09 higher odds of expressing fatigue compared to TT patients. Finally, patients with at least one C allele for CLOCK SNP tended to display higher fatigue levels than TT patients. CONCLUSIONS: Our study showed that anemic breast cancer patients with a high number of chemotherapy cycles and those carrying at least one C allele for DRD2 and CLOCK SNPs are at greater risk of exhibiting fatigue. Since no previous research has reported such genetic results, future studies are necessary to confirm our findings.

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.

Mechanisms of new-onset psychosis during the COVID-19 pandemic: What ignited the fire?

BACKGROUND: The coronavirus disease 2019 (COVID-19) pandemic has been associated with the emergence of various psychiatric illnesses, although very little literature has focused on the effect of COVID-19 on psychosis. Preliminary data have shown possible increases in new-onset psychosis. METHODS: Using MEDLINE, we performed a review of the current literature to identify the mechanisms by which pandemics may increase psychosis risk and generate evidence-based recommendations to control surges of psychosis. We identified 85 relevant studies, of which 34 were case reports on psychosis during the COVID-19 pandemic. RESULTS: Underlying mechanisms of psychosis include "direct viral mechanisms," such as neuroinflammation linked with the coronavirus, and "nonviral mechanisms," such as stress, isolation, and uncertainty. CONCLUSIONS: Improvement of our understanding of the pathophysiology of psychosis related to COVID-19 along with implementation of strategies to fight against stress and social isolation in addition to awareness campaigns regarding new-onset psychotic symptoms are much needed to optimize early detection and management of psychosis.

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 anxiety and depression in breast cancer patients: a cross-sectional study.

BACKGROUND: Despite the progress in assessment and treatment of breast cancer, being diagnosed with it or receiving chemotherapy treatment is still conceived as a traumatic experience. Women develop negative thoughts about life and death with detrimental effects on their daily physical functioning/activities, emotional state and overall quality of life. The aim of our study was to evaluate the level of anxiety and depression among breast cancer patients receiving chemotherapy and explore the correlation between these psychological disorders, clinical, sociodemographic and genetic factors. METHODS: A cross-sectional study was conducted among breast cancer patients undergoing intravenous chemotherapy at the oncology outpatient unit of Hôtel-Dieu de France hospital (November 2017-June 2019; Ethical approval number: CEHDF1016). All patients gave their written informed consent and completed several validated scales, including the Hospital Anxiety and Depression scale (HADS) for the assessment of anxiety and depression. Sleep quality, insomnia, cognitive function, fatigue and pain were also evaluated. Genotyping for certain gene polymorphisms (CLOCK, PER2, CRY2, OPRM1, ABCB1, COMT, DRD2) was performed using the Lightcycler® (Roche). RESULTS: A total of 112 women was included. The prevalence of depression was 43.4%, and 56.2% of the patients reported anxiety (based on the HADS classification). Multivariable analysis showed that higher cognitive scores and taking fosaprepitant were significantly associated with lower depression and anxiety scores. Moreover, being married compared to single was also associated with lower depression scores, whereas higher PSQI scores (worse sleep quality) and having the PER2 AA variant genotype compared to GG were significantly associated with higher depression scores. Finally, reporting a more severe insomnia and having the COMT Met/Met genotype were significantly associated with a higher anxiety score. CONCLUSIONS: Our study demonstrated a strong relationship between depression scores and cognitive impairment, sleep quality, marital status, fosaprepitant intake, and PER2 polymorphism, while anxiety scores were correlated to cognitive impairment, insomnia severity, fosaprepitant intake, and COMT polymorphism. The association with PER polymorphism was not previously reported. Identification of genetic and clinical risk factors for anxiety and depression would help clinicians implement an individualized management therapy aiming at preventing and alleviating the burden of these symptoms in breast cancer patients, hence improving their overall quality of life.

Characteristics of Older Adult First-Time Sex Offenders: Insights From the Missouri Registry.

OBJECTIVE: To explore the characteristics of older adult first-time sex offenders (who offended for the first time at the age of 65 years or above). DESIGN: The authors retrieved and analyzed data from the publicly available Missouri sex offender registry database up to December 2018 and the Missouri public case management system website. PARTICIPANTS: Registered older (≥65 years) sex offenders in the state of Missouri, United States. MEASUREMENTS: Sociodemographic characteristics of the offender, offense type(s), offense, and conviction dates; age and sex of the victim(s); and case disposition information (whether the trial was waived or not and what were the sentences imposed). RESULTS: One hundred and ninety-four older adult sex offenders all males were identified, of which 172 were first-time offenders. The majority were white; the median age of offense was 68.6 years old. One hundred and thirty-nine (80.8%) first-time offenders were convicted strictly of non-pornography offenses, with prepubescent girls the predominant victim pool. The most prevalent charge in this subgroup was Child Molestation, First Degree (36.5%). Twenty-eight (16.3%) offenders were convicted strictly of pornography offenses, the most prevalent one being Possession of Child Pornography (96.6%). The recidivism rate among first-time offenders was close to 1%. CONCLUSION: A substantial proportion of older registered sex offenders are first-time sex offenders and most of them have underage victims. Although the offense and recidivism rates seem to be low, future longitudinal studies should focus on the predictors of sexual offending in the older population, in order to design targeted preventive measures, risk assessment, and treatment options.

Rational deprescribing in the elderly.

BACKGROUND: Polypharmacy, defined as being prescribed 5 or more medications, has been shown to be associated with a decline in mental and physical functioning in elderly patients. Despite this, elderly patients are currently being prescribed a median of 7 medications, which often causes more harm than benefit, and emphasizes the importance of deprescribing. METHODS: Five classes of potentially inappropriate medications for the elderly population, especially for the aging brain, are discussed, including anticholinergics, benzodiazepines, antipsychotics, opioids, and proton pump inhibitors. Recommendations regarding these medications were collected from the 2015 Beer's Criteria, the Screening Tool of Older Person's Prescriptions (STOPP) criteria, the Screening Tool to Alert doctors to the Right Treatment (START) criteria, and the Fit fOR The Aged (FORTA) list. The PubMed database was also searched for the most recent evidence regarding prescription patterns, adverse effects, and recommendations regarding discontinuation of these medications in older adults. RESULTS: Anticholinergics, benzodiazepines, antipsychotics, and opioids were all found to have significant adverse effects in the elderly population. All of the discussed medication classes have been shown to be successfully deprescribable. CONCLUSIONS: Polypharmacy increases the risk of adverse drug reactions and hospitalizations in geriatric patients. Rational deprescribing of anticholinergics, benzodiazepines, antipsychotics, opioids, and proton pump inhibitors in selected patients may be a good first step to reducing this risk.

Prevalence and Correlates of Criminal Behavior Among the Non-institutionalized Elderly: Results From the National Survey on Drug Use and Health.

OBJECTIVES: First to explore the prevalence of criminal behavior committed by the non-institutionalized geriatric American population. Second to determine the correlates of criminal behavior among this population. METHODS: We used data of the non-institutionalized adults aged ≥65 years in the National Survey on Drug Use and Health from 2008 through 2014. We compared socio-demographic and mental health profiles of arrestees to non-arrestees and lawbreakers to non-lawbreakers and then determined the correlates of being arrested and breaking the law through regression analyses. RESULTS: Around 0.4% of the population reported being arrested, and 5% reported breaking the law in the past year. The most prevalent offense was driving while intoxicated. Arrestees were significantly more likely to be male and to have had an alcohol or a drug(s) use disorder in the past year. Lawbreakers had a significant likelihood of being male, having a high educational level, and having an alcohol or a drug(s) use disorder in the past year. CONCLUSIONS: Elderly lawbreakers seem to have distinct characteristics that not just separate them from non-offenders but also probably from younger lawbreakers.

Empathy changes in neurocognitive disorders: A review.

BACKGROUND: Empathy can be broadly defined as the ability to understand what others feel (cognitive empathy) and feel what others feel (affective empathy). The capacity to empathize may be impaired in certain major neurocognitive disorders (MNCDs), affecting not only the patient, but also the caregivers. METHODS: PubMed and Google Scholar databases were searched for studies investigating empathy changes, using an objective scale, in patients with MNCDs. RESULTS: The Interpersonal Reactivity Index was most commonly used to evaluate empathy in this population. Impairments in cognitive but not affective empathy were found in patients with Alzheimer's disease (AD), and may be attributable to overall cognitive decline. Patients with frontotemporal dementia (FTD) have demonstrated severe deficits in empathy, correlating with greater caregiver burden. Empathy changes in patients with dementia with Lewy bodies, vascular dementia, and Parkinson's disease dementia have not yet been studied. Intranasal oxytocin has emerged as a promising therapeutic approach for empathy loss, but it has not been explored yet in patients with MNCDs. CONCLUSIONS: Caregivers need to be educated about empathy loss, which is an important part of the disease process in AD and FTD. Future research should further assess empathy changes in other MNCDs, as well as explore novel treatment options in this field.