Comparing end-of-life care of hematologic malignancy versus solid tumor patients in a tertiary care center.

OBJECTIVES: To compare end-of-life (EOL) care for solid tumor and hematologic malignancy (HM) patients. METHODS: We collected data on the last 100 consecutive deceased HM and 100 consecutive deceased solid tumor patients who died prior to June 1st 2020, treated at a single center. We compared demographic parameters, cause of death as ascertained by review of medical records by two independent investigators, and EOL quality indicators including: place of death, use of chemotherapy or targeted/biologic treatment, emergency department visits as well as hospital, inpatient hospice and Intensive Care Unit admissions and the time spent as inpatient over the last 30 days of life; mechanical ventilation and use of blood products during the last 14 days of life. RESULTS: In comparison with solid tumor patients, HM patients more commonly died from treatment complications (13% vs. 1%) and unrelated causes (16% vs. 2%, p < .001 for all comparisons). HM patients died more frequently than solid tumor patients in the intensive care unit (14% vs. 7%) and the emergency department (9% vs. 0%) and less frequently in hospice (9% vs. 15%, p = .005 for all comparisons). In the 2 weeks prior to death HM patients were more likely than solid tumor patients to undergo mechanical ventilation (14% vs. 4%, p = .013), receive blood (47% vs. 27%, p = .003) and platelet transfusions (32% vs. 7%, p < .001); however, no statistical difference was found in use of either of chemotherapy (18% vs. 13%, p = .28) or targeted treatment (10% vs. 5%, p = .16). CONCLUSIONS: HM patients were more likely than solid tumor patients to undergo aggressive measures at EOL. Rarity of HM deaths, frequently caused by complications of treatment and unrelated causes, may affect treatment choices at EOL.

Preclinical In-Vivo Safety of a Novel Thyrotropin-Releasing Hormone-Loaded Biodegradable Nanoparticles After Intranasal Administration in Rats and Primates.

Thyrotropin-releasing hormone (TRH) and TRH-like peptides carry a therapeutic potential for neurological conditions. Nanoparticles (NP) made of the biodegradable polymer, Poly(Sebacic Anhydride) (PSA), have been developed to carry TRH, intended for intranasal administration to patients. There is limited information on the safety of biodegradable polymers when given intranasally, and therefore, we have performed two preclinical safety and toxicity studies in cynomolgus monkeys and rats using TRH-PSA nanoparticles. The rats and monkeys were dosed intranasally for 42 days or 28 days, respectively, and several animals were followed for additional 14 days. Animals received either placebo, vehicle (PSA), or different concentrations of TRH-PSA. No systemic adverse effects were seen. Changes in T3 or T4 concentrations were observed in some TRH-PSA-treated animals, which did not have clinical or microscopic correlates. No effect was seen on TSH or prolactin concentrations. In the monkey study, microscopic changes in the nasal turbinates were observed, which were attributed to incidental mechanical trauma caused during administration. Taken together, the TRH-loaded PSA NPs have proven to be safe, with no local or systemic adverse effects attributed to the drug loaded nanoparticles. These findings provide additional support to the growing evidence of the safety of peptide-loaded NPs for intranasal delivery and pave the way for future clinical trials in humans.

Paclitaxel Delivery to the Brain for Glioblastoma Treatment.

The development of paclitaxel-loaded polymeric nanoparticles for the treatment of brain tumors was investigated. Poly(lactide-glycolide) (PLGA) nanoparticles containing 10% w/w paclitaxel with a particle size of 216 nm were administered through intranasal and intravenous routes to male Sprague-Dawley rats at a dose of 5 mg/kg. Both routes of administration showed appreciable accumulation of paclitaxel in brain tissue, liver, and kidney without any sign of toxicity. The anti-proliferative effect of the nanoparticles on glioblastoma tumor cells was comparable to that of free paclitaxel.

Depression, hope and social support among older people with cancer: a comparison of Muslim Palestinian and Jewish Israeli cancer patients.

OBJECTIVES: Studies of depression in older Muslim Palestinians diagnosed with cancer are scarce. To gain insight into the psychological response and coping ability of this very large, globally distributed population, we collected data from older Muslim Palestinian people diagnosed with cancer concerning depression hope and perceived social support. Both hope and social support were selected because they can be manipulated through intervention and education, as shown in the geriatric literature. Data were compared to data collected from older Jewish Israeli people diagnosed with cancer. DESIGN: The study sample comprised 143 Muslim Palestinian and 110 Jewish Israeli people diagnosed with cancer, aged ≥ 65. All participants were either in treatment for active disease or within 6 months of such treatment. Self-administered measures included depression (the Five-Item Geriatric Depression Scale), perceived social support (Cancer Perceived Agents of Social Support Questionnaire) and hope (Snyder's Adult Hope Scale). RESULTS: Hope and depression were both found to be significantly higher among the Muslim Palestinian patients than in the Jewish Israeli participants. In both samples, higher levels of hope were associated with lower levels of depression, with this correlation stronger in the Jewish Israeli group. CONCLUSION: To improve the psychological wellbeing of patients, healthcare providers must exercise cultural sensitivity in their interactions, respecting the perspectives of both the patients and their families. Incorporating the concept of hope into the therapeutic dialogue and language may improve psychological wellbeing and synchronize the needs and expectations of patients, caregivers, and healthcare professionals, resulting in more equitable, effective and value-oriented care.

Predictors of death at home among cancer patients in Israel: a population-based study.

BACKGROUND: Most cancer patients prefer to die at home; however, many die in hospital. The aim of the current study is to elucidate the association between dying at home and various personal factors in the Israeli population of cancer patients. METHODS: Data on cancer incidence (2008-2015) and death (2008-2017) was provided by the Israeli Central Bureau of Statistics and the Israel National Cancer Registry. Binary logistic regression analyses were performed to assess odds ratios for death at home following cancer diagnosis while controlling for age, sex, ethnicity, years of education, residential socioeconomic score, and time from diagnosis. We also assessed the relation between place of death and specific cancer sites, as well as the time trend from 2008 to 2017. RESULTS: About one quarter (26.7%) of the study population died at home. Death at home was most frequent among patients diagnosed with brain tumors (37.0%), while it was the lowest among patients with hematologic malignancies (lymphoma and leukemia, 20.3 and 20.0%, respectively). Rates of dying at home among patients with residential socioeconomic scores of 1, 2-9, and 10 were about 15, 30, and 42.9%, respectively. In patients from the 4th to the 7th decades of life, rates of death at home increased at a linear rate that increased exponentially from the 8th decade onwards. After controlling for potential confounders, predictive variables for death at home included age (OR = 1.020 per year, 95% CI 1.017-1.024), male sex (OR = 1.18, 95% CI 1.077-1.294), years of education (OR = 1.029 per year, 95% CI 1.018-1.040), and time from diagnosis (OR = 1.003 per month, 95% CI 1.001-1.005 all p < 0.001). No trend was seen from 2008 to 2013, while from 2014 to 2017 a slight increase in the rate of death at home was seen each year. CONCLUSIONS: These results indicate wide variability in death at home exists among patients of different ages, sex, education, socioeconomic status and time from diagnosis. These findings stress the importance of delivering quality palliative care at home, mainly for patients with hematologic malignancies, younger patients, and patients of very low socioeconomic status. Understanding the complex mechanisms whereby patient preferences and the above variables may determine the preferred place of death remains an important research priority.

Informal caregivers of older Muslims diagnosed with cancer: A portrait of depression, social support, and faith.

OBJECTIVE: Islamic population constitute more than 20% of the world population and is growing rapidly. Nevertheless, data concerning informal caregiving to older Muslim patients diagnosed with cancer are scarce. Improving the well-being of caregivers is a vital step to optimal care for the patients themselves throughout the Muslim community and the world. This study focuses on a sample of Palestinian caregivers of older Muslim patients diagnosed with cancer living in East Jerusalem, the West Bank, and Gaza. The study aims to describe the socio-demographic characteristics of the caregivers and to understand their social support, and identify predictors of caregivers' depression. METHODS: A cross-sectional study of a convenience sample of 99 dyads of Palestinian patients (age ≥65) and their informal caregivers. Depression and social support were measured using the five items of the Geriatric Depression Scale and the Cancer Perceived Agents of Social Support questionnaire. RESULTS: Caregivers were most frequently adult children (52%) or spouses (32%), with male patients cared for by spouses (47.5%) or sons (32%), and female patients by daughters (50%). Clinical levels of depression were reported by 76% of the caregivers and 85% of patients. The significant predictors of caregiver depression were female gender, lower education, lower perceived social support from spouse and family, and higher perceived support from faith. SIGNIFICANCE OF RESULTS: Healthcare providers serving the study population should determine the position and role of the caregiver within the social and family structure surrounding the patients' families. This understanding may facilitate overcoming barriers to effective and meaningful social support.

[LONELINESS, FUNCTION AND LONGEVITY: THE JERUSALEM LONGITUDINAL COHORT STUDY].

AIMS: To assess the association between subjective loneliness among the elderly (whether an individual feels lonely) with functional status and longevity after adjustment for potential confounders. BACKGROUND: While objective measures of loneliness among older people have been found to be associated with functional decline and increased mortality, little is known concerning the relationship between subjective loneliness, function, morbidity and longevity. METHODS: Subjective loneliness, health variables, functional status and mortality were assessed through the Jerusalem Longitudinal Cohort Study (1990-2015), a prospective longitudinal study. Participants born between the years 1920-1921 were assessed at home at ages 70, 78, 85 and 90. Depressed participants were excluded from the statistical analyses. Participants were asked how often they felt lonely, with answers dichotomized to never versus rarely/often/very often. RESULTS: At age 70, 78, 80 and 90, overall prevalence of loneliness was 27.8% , 23.7% , 23.9% and 26.7% respectively. Male gender and not being married were consistently associated at all ages with increased likelihood of loneliness. After adjusting for baseline variables, we found no association between subjective loneliness and subsequent deterioration in functional status, cognitive function (decline in mini-mental score<24) or chronic pain in any age groups. Furthermore, loneliness was not associated with mortality among the participants between ages 70-78, 78-85, 85-90 and 90-95. We repeated all the analyses, this time including depressed subjects, with no significant change in the overall findings. CONCLUSIONS: Loneliness was not associated with subsequent poor health outcomes or decline in functional status up to the age of 95. Furthermore, no association was found between subjective loneliness and mortality at any age.

Adolescent overweight and obesity and the risk for pancreatic cancer among men and women: a nationwide study of 1.79 million Israeli adolescents.

BACKGROUND: There is growing concern regarding the impact of adolescent obesity on adult health. The objective of this study was to evaluate the association between body mass index (BMI) in late adolescence and the incidence of pancreatic cancer during adulthood. METHODS: The authors analyzed a cohort of 1087,358 Israeli Jewish men and 707,212 Jewish women who underwent a compulsory physical examination between ages 16 and 19 years from 1967 to 2002. Pancreatic cancer incidence through December 31, 2012 was identified by linkage to the national cancer registry. Multivariable-adjusted Cox regression was used to estimate hazard ratios (HRs) for pancreatic cancer according to the US Centers for Disease Control and Prevention (CDC) BMI percentiles at baseline. RESULTS: Over a median 23 year follow-up, 551 incident cases of pancreatic cancer cases occurred (423 men; 128 women). Compared with normal weight (5th to-<85th percentile), obesity (≥95th percentile) was associated with an increased risk of cancer among both men (HR, 3.67; 95% confidence interval [CI], 2.52-5.34) and women (HR, 4.07; 95% CI, 1.78-9.29). Among men, compared with low-normal BMI (≥5th to <25th percentile), high-normal BMI (≥75th to <85th percentile) and overweight (85th to 95th percentile) also were associated with a higher risk for cancer(high-normal BMI: HR, 1.49; 95% CI, 1.05-2.13; overweight: HR, 1.97; 95% CI, 1.39-2.80). The estimated population-attributable fraction because of overweight and obesity was 10.9% (95% CI, 6.1%-15.6%). CONCLUSIONS: Men and women who were obese or overweight as adolescents are at an increased risk for subsequent pancreatic cancer.

Temporal trends of geographic variation in mortality following cancer diagnosis: a population-based study.

BACKGROUND: Inequalities among the western population, combined with the introduction of new treatment options for cancer, have challenged endeavors to provide equal care to patients with cancer. Israel's highly developed healthcare system and mandatory National Health Insurance afforded an opportunity to study geographic variation over time in mortality following cancer diagnosis. METHODS: This historical prospective cohort study included a nationally representative cohort that was assessed by the Israeli Central Bureau of Statistics 1995 census and followed until 2011. The cancer incidence (1995-2009) was ascertained by the Israel National Cancer Registry. We analyzed the effect on patient outcome of living in a given district, according to the Israeli Central Bureau of Statistics classification. Patients were stratified by the year of diagnosis (1995-1997, 1998-2000, etc.), and associations were adjusted for age, ethnicity, and districts. We excluded patients with malignancies associated with screening program (breast, prostate, colon, and cervical cancers). RESULTS: This study included 26,173 patients living in 13 residential districts. During the last years (2007-2009) of the study, the hazard ratio (HR) for risk of death was high in 8/13 districts (61.5%), compared to 4/13 (30.7%) during 2004-2006, and 0/13 (0%) during 2001-2003. Districts that were less likely to be associated with increased risk of death were located in the center of Israel and in metropolitan areas, compared to the peripheral regions. Furthermore, HRs were substantially higher in the last years of the study (2007-2009, HRs rose to 1.69, 95%CI: 1.38-2.08) compared to the earlier years (2004-2006, HRs rose to 1.35, 95%CI: 1.13-1.62). CONCLUSION: Our findings suggested that geographic variation for mortality following cancer diagnosis have increased over time. Our results provide policy makers with vital information regarding the need for targeted interventions, mainly in peripheral regions.

Risk of nasopharyngeal carcinoma penetrates across immigrant generations: A migrant cohort study of 2.3 million Jewish Israeli adolescents.

Nasopharyngeal cancer (NPC) incidence varies widely across geographic regions and ethnic groups. We conducted a large-scale migrant cohort study to assess origin and migrant generation as predictors of NPC, controlling for possible confounders. Data on 2.3 million Jewish Israeli adolescents, who underwent a compulsory general health examination at ages 16-19 between the years 1967 and 2011 were linked to the Israel National Cancer Registry to obtain incident NPC up to 2012. Cox proportional hazards were used to model time to event. During 46.5 million person-years of follow-up, 276 incident cases were identified. Origin was a strong independent predictor of NPC with high rates for first generation North African born (adjusted HR 5.52; 95% CI 2.43-12.52; p < 0.000044) and Asian born (adjusted HR 3.79; 95% CI 1.43-10.00; p = 0.007) compared to European-born, adjusted for sex, year of birth, residential socio-economic position, years of education, rural residence, body mass index and height. The magnitude of the associations was similar in the Israeli-born of North African and Asian origin, with these second and third generation immigrants showing elevated HRs (adjusted HR 6.09; 95% CI 2.81-13.20; p = 4.72.10-6 and 3.86; 95% CI 1.77-8.41; p = 0.00067, respectively). These findings suggest a strong genetic predisposition and/or efficient cultural transmission of environmental exposures in the etiology of NPC.

A Dialogue of Depression and Hope: Elderly Patients Diagnosed with Cancer and Their Spousal Caregivers.

In the next few decades, a significant increase in the number of elderly survivors diagnosed with cancer is anticipated due to an increase in life expectancy and better medical treatments. The reality of being old and being diagnosed with cancer may limit considerably the future time perspective (time expected to live) of both the patient and his or her caregiver(s) and lead then to invest resources in emotionally meaningful goals and close social relationships. The goal of the current study was to describe the relationship among psychological distress, depression, social support, and hope in a cohort of oldest old patients diagnosed with cancer and their spousal caregivers living at home. We predicted that patients would rely mostly on their hope and less on social as a source of coping. Our cross-sectional sample consisted of 45 patients with cancer and 45 spouses; all individuals were at least 86 years old. The participants completed standardized self-report measures of depression, distress, hope, and social support. Patients presented extremely high levels of psychological distress compared with their spousal caregivers, who exhibited significantly lower levels of distress and depression. Among patients, hope but not social support was found to be negatively correlated to distress. In order to enhance the quality of life of oldest old cancer patients and their spouses, health care teams should understand and address the unique needs of each individual within the dyads of patients and spouses in this group.

Hope and social support in elderly patients with cancer and their partners: an actor-partner interdependence model.

AIM: Assess relationships between oldest-old (minimum 86 years) patients' perceived social support to their own and their spousal caregivers' hope through application of the actor-partner interdependence model (APIM). PATIENTS & METHODS: 58 dyads of patients and their spousal caregivers completed standardized self-report measures of depression, distress, hope and social support. RESULTS: Patients presented high distress levels. Among patients and spouses, perceived social support was positively correlated to their own level of hope (ß = 0.44, p < 0.0001; ß = 0.56, p < 0.0001, respectively) and negatively correlated to the other's level of hope (ß = -0.25, p < 0.024; ß = -0.44, p < 0.0001, respectively). CONCLUSION: The actor-partner interdependence model was found to be adequate for describing relationships between social support and hope among dyads of oldest-old patients and their spousal caregivers. Patients and caregiver seem to utilize social support to enhance hope.

Silent Partners to Cancer Patients: Formal Caregivers and Oncologists.

Given the worldwide aging of the population, the projected increase of older people diagnosed with cancer, and the changes in the structure of society and family, it is predictable that larger numbers of aged cancer patients will be supported by formal caregivers. This exploratory study attempts to gain insight into and to make recommendations to oncologists based on the comparison of two groups of foreign formal caregivers-those providing care to elderly cancer patients and those providing care to the elderly suffering from other chronic illnesses. Our sample included 108 Filipino formal caregivers to older persons (age 65+) suffering from cancer or other chronic diseases. Participants completed a short questionnaire targeting background information, subjective perception of distress, attachment to the care recipient family, and the Distress Thermometer. Participants reported extreme levels of distress, with only seven (6.48%) scoring less than 5 on the Distress Thermometer. Caregivers to cancer patients reported significantly higher levels of distress and tended to feel less attached to the family of the patient in comparison to caregivers to patients with other chronic illnesses. Cultural differences regarding cancer among the elderly may explain the higher levels of distress reported among Filipino formal caregivers and need to be acknowledged by oncologists. As a precondition for simultaneously improving the caregiver's well-being and the patient's quality of care, it is recommended that oncologists relate directly to formal caregivers, specifically to their extreme distress and apprehension regarding cancer.

Effects of aquatic exercise program versus on-land exercise program on cancer-related fatigue, neuropathy, activity and participation, quality of life, and return to work for cancer patients: study protocol for a randomized controlled trial.

BACKGROUND: Exercise has shown positive effects on fatigue, exhaustion, neuropathy, and quality of life in cancer patients. While on-land exercises have been studied, the aquatic environment offers unique advantages. Water's density and viscosity provide resistance, enhancing muscle strength, while hydrostatic pressure improves venous return. This trial aims to investigate the effect of aquatic exercises on time to return to work, work hours, work-related difficulties, daily life activity and participation, quality of life, exhaustion, fatigue, and neuropathy among cancer patients, compared to on-land exercise intervention group and a non-exercise group. METHODS: This randomized controlled trial will include 150 cancer patients aged 18-65 years with stage III colon cancer or breast cancer patients with lymph node involvement. Participants in the aquatic exercise intervention group will undergo an 8-week, twice-weekly group-based Ai-Chi program, while the on-land exercise group will perform identical exercise. The control group will not engage in any exercise. The primary outcome will be assessed using an employment barriers questionnaire, capturing return to work date and working hours and daily life participation and activity and quality of life. Secondary outcomes include exhaustion, fatigue, and neuropathy. Data will be collected at baseline, post-intervention (8 weeks), and at 3,12, and 24 months. Mixed variance analyses will explore relationships among groups and over time for independent variables, with separate analyses for each dependent variable. DISCUSSION: The potential benefits include an earlier return to work for patients, reducing their need for social and economic support. The study's implications on socio-economic policies are noteworthy, as a successful intervention could offer a cost-effective and non-invasive solution, improving patients' quality of life and increasing their participation in daily activities. This, in turn, could lead to a faster return to work, contributing to both personal well-being and broader societal interests by reducing reliance on social services. TRIAL REGISTRATION: The trial is registered at ClinicalTrials.gov NCT05427344 (22 June 2022).

Multimodal Machine Learning for Prediction of 30-Day Readmission Risk in Elderly Population.

BACKGROUND: Readmission within 30 days is a prevalent issue among elderly patients, linked to unfavorable health outcomes. Our objective was to develop and validate multimodal machine learning models for predicting 30-day readmission risk in elderly patients discharged from internal medicine departments. METHODS: This was a retrospective cohort study which included elderly patients aged 75 or older, who were hospitalized at the Hadassah Medical Center internal medicine departments between 2014 and 2020. Three machine learning algorithms were developed and employed to predict 30-day readmission risk. The primary measures were predictive model performance scores, specifically area under the receiver operator curve (AUROC), and average precision. RESULTS: This study included 19,569 admissions. Of them, 3258 (16.65%) resulted in 30-day readmission. Our 3 proposed models demonstrated high accuracy and precision on an unseen test set, with AUROC values of 0.87, 0.89, and 0.93, respectively, and average precision values of 0.76, 0.78, and 0.81. Feature importance analysis revealed that the number of admissions in the past year, history of 30-day readmission, Charlson score, and admission length were the most influential variables. Notably, the natural language processing score, representing the probability of readmission according to a textual-based model trained on social workers' assessment letters during hospitalization, ranked among the top 10 contributing factors. CONCLUSIONS: Leveraging multimodal machine learning offers a promising strategy for identifying elderly patients who are at high risk for 30-day readmission. By identifying these patients, machine learning models may facilitate the effective execution of preventive actions to reduce avoidable readmission incidents.

Outcomes of extracranial stereotactic body radiation therapy for induced oligometastatic non-small cell lung cancer on novel systemic therapy.

Background: Stereotactic body radiation therapy (SBRT) is often delivered in patients with oligometastatic disease (OMD). However, the specific subset of patients with polymetastatic non-small cell lung cancer (NSCLC) on novel systemic therapies who develop induced oligopersistant disease (OpersisD) or oligoprogressive disease (OprogD), as defined by the European Organisation for Research and Treatment of Cancer (EORTC) OMD classification, has not been well described. This study explores the outcomes of patients treated with this strategy. Methods: Patients with stage IV NSCLC being treated with osimertinib or immune checkpoint inhibitors (ICIs) who received extracranial SBRT for OpersisD or OprogD were identified in our retrospective analysis. Outcomes reported include progression-free survival (PFS), time to change of systemic treatment (TTCST), overall survival (OS), local control (LC) and treatment-related toxicity. Results: Forty-nine patients received SBRT for OpersisD (34.7%) or OprogD (65.3%) at a median of 5.8 and 15.3 months after start of systemic therapy, respectively. 55.1% received concurrent osimertinib and 44.9% received ICI. Seventy-seven extracranial lesions were treated with various fractionation schemas. At a median of 18.8 months follow-up from first SBRT, LC was achieved in 92.2% of total lesions treated (71). The 1-year OS was 91.7% for OpersisD and 83.3% for OprogD. OpersisD compared to OprogD had a longer median PFS (18.3 vs. 6.1 months) and longer median TTCST (23.6 vs. 13.5 months), median OS was not reached for either cohort. On multivariate analysis, patients treated with osimertinib had shorter PFS (HR: 2.20; 95% CI: 1.01-4.82; P=0.048) and shorter TTCST (HR: 2.83; 95% CI: 1.09-7.33; P=0.032). One patient (2%) experienced grade 3 pneumonitis after SBRT, and no grade 4-5 toxicities were reported with SBRT treatment. Conclusions: This study indicates that SBRT for OpersisD or OprogD in Stage IV NSCLC patients on osimertinib or ICIs is safe, very well tolerated, and may prolong the time before needing a shift in systemic therapy. Further prospective research is needed to validate and expand upon these findings.

Late life depression and concepts of aging: an emerging paradigm.

Late life depression (LLD) is an emerging challenge, and recognized as a significant barrier to long-term healthy aging. Viewed within the context of the medical/biological model, advances in brain sciences over the last several decades have led to a deeper understanding of the biology of LLD. These advances in current knowledge include the description of aging brain pathophysiology; the biology and biochemistry of neurotransmitters; the correspondence between changes in neurological structure, function, and neural network; the description of neural, hormonal and inflammatory biomarkers; and identification of typical phenotypic subtypes of LLD. Despite these advances, current treatment of LLD, which remains largely pharmacological with accompanying cognitive and behavioral interventions, has poor success rate for long-term remission among older people. A wider perspective, in keeping with several emerging aging concepts, is suggested as an alternative framework within which to view LLD. A growing body of research supports the important role in LLD of frailty, resilience, intrinsic capacity, and functional integrity. Similarly, important social determinants need to be addressed in the etiology of LLD, rooted largely in negative stereotypes of aging, with consequent repercussions of reduced participation and inclusion, growing social isolation, with loss of identity, meaning and hope. This perspective suggests the importance of a wider integrative conceptualization of depression, set against a background of emerging aging concepts.

Driver mutation characteristics of phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA) in advanced non-small cell lung cancer.

OBJECTIVES: The identification and targeting of actionable genomic alterations (AGA) have revolutionized the treatment of cancer in general and mostly for non-small cell lung cancer (NSCLC). We investigated whether in NSCLC patients PIK3CA mutations are actionable. MATERIALS AND METHODS: Chart review was performed of advanced NSCLC patients. PIK3CA mutated patients were analyzed as two groups: Group A: without any non-PIK3CA established AGA; Group B: with coexisting AGA. Group A was compared to a cohort of non-PIK3CA patients (group C), using t-test and chi-square. To evaluate the impact of PIK3CA mutation on outcome, we compared Group A survival to age/sex/histology matched cohort of non-PIK3CA mutated patients (group D) by Kaplan-Meier method. A patient with a PIK3CA mutation was treated with a PI3Ka-isoform selective inhibitor BYL719 (Alpelisib). RESULTS: Of a cohort of 1377 patients, 57 are PIK3CA mutated (4.1%). Group A: n-22, group B: n-35. Group A median age is 76 years, 16 (72.7%) men, 10 (45.5%) squamous, 4 (18.2%) never smokers. Two never-smoker female adenocarcinoma patients had solitary PIK3CA mutation. One of them was treated with a PI3Ka-isoform selective inhibitor BYL719 (Alpelisib), with rapid clinical and partial radiological improvement. Group B, compared with Group A, included younger patients (p = 0.030), more females (p = 0.028) and more adenocarcinoma cases (p < 0.001). Compared to group C, group A patients were older (p = 0.030) and had more squamous histology (p = 0.011). CONCLUSION: In a small minority of NSCLC patients with PIK3CA mutation there are no additional AGA. PIK3CA mutations may be actionable in these cases.

Clinical Characteristics, Response to Platinum-Based Chemotherapy and Poly (Adenosine Phosphate-Ribose) Polymerase Inhibitors in Advanced Lung Cancer Patients Harboring BRCA Mutations.

The oncogenic role and clinical relevance of BRCA mutations in NSCLC remain unclear. We aim to evaluate the characteristics and clinical outcomes of patients with NSCLC harboring BRCA mutations treated at Hadassah Medical Center (HMC). We retrospectively assessed all patients with advanced NSCLC who underwent next-generation sequencing (NGS) and were found to have pathogenic somatic BRCA mutations (p-BRCA). We compared clinical outcomes in NSCLC patients with wild-type BRCA (wt-BRCA) matched by age, stage, gender, smoking, PDL-1 and driver mutations. Between 2015 and 2022, we evaluated 598 patients with advanced NSCLC using NGS and found 26 patients with p-BRCA, of whom 17 (65.4%) were carriers of germline BRCA variants and represented 1% of all BRCA carriers HMC. The median age of diagnosis was 67 years old (40-78), 13 patients (50%) had a history of smoking and 9 patients (34.6%) had additional driver mutations (EGFR, ALK, BRAF, MET or ERBB2). Objective response rate and median progression-free survival (PFS) for first-line platinum-based chemotherapy in the p-BRCA group compared to wt-BRCA controls were 72.2% and 16 months (CI 95%, 5-22), compared to 47.4% and 7 months (CI 95%, 5-9), respectively, and HR for PFS was 0.41 (CI 95%, 0.17-0.97). Six patients in the p-BRCA group were treated with advanced-line poly (adenosine-phosphate-ribose) polymerase inhibitors (PARPi), with a durable response observed in four patients (66%). In this cohort, patients with NSCLC harboring p-BRCA exhibit high-sensitivity PARPi and a prolonged response to platinum, suggesting some oncogenic role for BRCA mutations in NSCLC. The results support further prospective trials of the treatment of NSCLC harboring p-BRCA with PARPi.

UNcommon EGFR Mutations: International Case Series on Efficacy of Osimertinib in Real-Life Practice in First-LiNe Setting (UNICORN).

INTRODUCTION: Approximately 10% of EGFR mutations (EGFRmuts) are uncommon (ucEGFRmuts). We aimed to collect real-world data about osimertinib for patients with ucEGFRmuts. METHODS: This is a multicenter, retrospective study of ucEGFRmut (exon 20 insertions excluded) metastatic NSCLC treated with osimertinib as first EGFR inhibitor. The Response Evaluation Criteria in Solid Tumors and response assessment in neuro-oncology brain metastases brain objective response rate (ORR) were evaluated by the investigators. Median progression-free survival (mPFS), median overall survival, and median duration of response (mDOR) were calculated from osimertinib initiation. Mutations found at resistance were collected. RESULTS: A total of 60 patients were included (22 centers, nine countries), with median age of 64 years, 75% females, and 83% Caucasian. The largest subgroups were G719X (30%), L861Q (20%), and de novo Thr790Met (T790M) (15%). The ORR was 61%, mPFS 9.5 months, mDOR 17.4 months, and median overall survival 24.5 months. Regarding patients with no concurrent common mutations or T790M (group A, n = 44), ORR was 60%, mPFS 8.6 months, and mDOR 11 months. For G719X, ORR was 47%, mPFS 8.8 months, and mDOR 9.1 months. For L861Q, ORR was 80%, mPFS 16 months, and mDOR 16 months. For de novo T790M, ORR was 44%, mPFS 12.7 months, and mDOR 46.2 months. Compound EGFRmut including common mutations had better outcome compared with only ucEGFRmut. For 13 patients with a response assessment in neuro-oncology brain metastases-evaluable brain metastases, brain ORR was 46%. For 14 patients, rebiopsy results were analyzed: four patients with additional EGFR mutation (C797S, D585Y, E709K), three with new TP53 mutation, one with c-Met amplification, one with PIK3CA mutation, and one with neuroendocrine transformation. CONCLUSIONS: Osimertinib was found to have an activity in ucEGFRmut with a high rate of disease control systemically and intracranially. Several resistance mechanisms were identified. This report comprises, to the best of our knowledge, the largest data set of its kind.