Medical Students' Experience of a Patient's Death and Their Coping Strategies: A Narrative Literature Review.

The experience of a patient's death on medical students is powerful and may entail distress and anxiety. We review the experience of death and dying as perceived by medical students. Students are exposed to death and dying while dissecting cadavers in pre-clinical years, following patient death in clinical years, and commonly as a result of personal exposure. Students report sadness and anger in response to patient death, particularly following their first experience. The patient's identity and the student's past exposure to death were found to influence the way students experience death and dying. Coping methods may include conversation, reflection, and religion as well as detachment and avoidance. Although time and resources are invested in preparing students for a patient's death, many of them feel inadequately prepared. Greater understanding of and investment in processing medical students' experience of patient death may be helpful in their personal and professional development.

The association of medical, social, and normative factors with the implementation of end-of-life care practices.

BACKGROUND: End-of-life (EoL) care practices (EoLCP) are procedures carried out at the EoL and bear directly on this stage in the patient's life. Public support of these practices in Israel is far from uniform. Previous studies show that while ∼30% of participants support artificial respiration or feeding of terminally ill patients, 66% support analgesic treatment, even at the risk of shortening life. This study aimed to create a typology of six end-of-life care practices in Israel and assess the association of medical, social, and normative factors with the implementation of those practices. These practices included mechanical ventilation, artificial feeding, deep sedation, providing information to the patient and family caregivers, including family caregivers in EoL decision-making, and opting for death at home. METHODS: This cross-sectional study was performed as an online survey of 605 adults aged 50 or more in Israel, of which ~ 50% (n = 297) reported supporting a dying terminally ill relative in the last 3 years. Participants were requested to provide their account of the EoL process of their relative dying from a terminal illness in several aspects, as well as the EoL care practices utilized by them. RESULTS: The accounts of the 297 interviewees who supported a dying relative reveal a varied EoL typology. The utilization of end-of-life care practices was associated with the socio-normative beliefs of family caregivers but not with their socioeconomic status. Strong correlations were found between family caregiver support for three key practices (mechanical ventilation, artificial feeding, and family involvement in EoL) and the actual utilization of these practices in the care of dying patients. CONCLUSIONS: The findings portray an important image of equity in the utilization of EoLCP in Israel, as the use of these practices was not associated with socioeconomic status. At the same time, the study found substantial diversity in family caregivers' preferences regarding EoL care practices use not related to socioeconomic status. We believe that differences in preferences that do not lead to problems with equity or other important societal values should be respected. Accordingly, policymakers and health system leaders should resist calls for legislation that would impose uniform EoL practices for all Israelis. Instead, they should take concrete steps to preserve and enhance the widespread current practice of practitioners to adapt EoL care to the varied needs and preferences of Israeli families and cultural, social, and religious subgroups. These steps should include providing frameworks and tools for family caregivers to support their loved ones close to their deaths, such as educational programs, seminars, supportive care before and during the end of life of their loved ones, etc.

Honoring the moment of death: Lived experiences, practices, and rituals of internal medicine residents.

Given the limited information on physicians' practices at the time of pronouncing a patient's death, this study aimed to learn about the prevalence and purpose of internal medicine residents' practices, the obstacles to performing them and how they can be overcome. Responses to a questionnaire were analyzed using logistic regression, to compare respondents who did and did not have a ritual. Twenty-one interview transcripts were thematically analyzed. A total of 151 physicians responded to the questionnaire; 35 (22.3%) reported performing a private ritual at the time of patient death. Religious participants were 2.97 times more likely {CI: 1.18-7.41} to perform a ritual following a patient's death. Three main themes were found, indicating residents' need to pause and perform a practice to honor the patient, express their humanity, and cope with the overflow of emotions. Senior staff should support opportunities for residents to honor the moment of death.

Impact of Folinic Acid Dosing on Efficacy and Toxicity of High-Dose Methotrexate in Central Nervous System Lymphoma.

INTRODUCTION: High-dose methotrexate (HDMTX)-based regimens are the treatment of choice in primary central nervous system lymphoma (PCNSL). Folinic acid (FA) rescue is used to mitigate the toxic effects of MTX on normal cells. However, the optimal dosing of FA in PCNSL remains uncertain. METHODS: We analyzed the relationship between FA dosing and treatment efficacy and toxicity in a cohort of 36 PCNSL patients treated at our institute between the years 2014 and 2022. A combination of univariate and multivariate analyses using known prognostic factors were used to determine the association between FA dosing and treatment outcomes. RESULTS: We found that higher per-treatment cumulative FA doses were associated with inferior progression-free survival (PFS), with a hazard ratio (HR) of 2.2 for each 100 mg/m2 increase in FA dose. We identified a threshold of 350 mg/m2/treatment, above which there was a significant reduction in PFS. Notably, lower FA doses did not result in increased toxicity. CONCLUSION: Our findings suggest that optimizing FA dosing to avoid very high rescue doses may improve treatment outcomes in PCNSL patients receiving HDMTX. Further prospective studies are warranted to validate these findings.

Standardization of Molecular MRD Levels in AML Using an Integral Vector Bearing ABL and the Mutation of Interest.

Quantitative PCR for specific mutation is being increasingly used in Acute Myeloid Leukemia (AML) to assess Measurable Residual Disease (MRD), allowing for more tailored clinical decisions. To date, standardized molecular MRD is limited to typical NPM1 mutations and core binding factor translocations, with clear prognostic and clinical implications. The monitoring of other identified mutations lacks standardization, limiting its use and incorporation in clinical trials. To overcome this problem, we designed a plasmid bearing both the sequence of the mutation of interest and the ABL reference gene. This allows the use of commercial standards for ABL to determine the MRD response in copy number. We provide technical aspects of this approach as well as our experience with 19 patients with atypical NPM1, RUNX1 and IDH1/2 mutations. In all cases, we demonstrate a correlation between response and copy number. We further demonstrate how copy number monitoring can modulate the clinical management. Taken together, we provide proof of concept of a novel yet simple tool, which allows in-house MRD monitoring for identified mutations, with ABL-based commercial standards. This approach would facilitate large multi-center studies assessing the clinical relevance of selected MRD monitoring.

Acute palliative care models: scoping review.

OBJECTIVE: The goal of this scoping review is to identify the most commonly used models of palliative care delivery in acute care settings, their advantages and disadvantages, and to review existent research evidence in support of each model. METHODS: We conducted an extensive search using EMBASE, Medline, CINAHL and Pubmed, using various combinations of terms relating to models in palliative care and acute care settings. Data were analysed using tabular summaries and content analysis. RESULTS: 41 articles were analysed. Four models were identified: primary, consultative, integrative and hybrid models of palliative care. All four models have varying characteristics in terms of access to specialist palliative care; fragmentation of healthcare services; therapeutic relationships between patients and providers; optimal usage of scarce palliative care resources; timing of provision of palliative care; communication and collaboration between providers and clarity of provider roles. Moreover, all four models have different patient outcomes and healthcare utilisation. Gaps in research limit the ability to determine what model of care is more applicable in an acute care setting. CONCLUSION: No ideal model of care was identified. Each model had its advantages and disadvantages. Future work is needed to investigate which setting one model may be better than the other.

Clonal Myeloid Dysplasia Following CAR T-Cell Therapy: Chicken or the Egg?

Multiple myeloma (MM) is characterized by recurrent relapses. Consequently, patients receive multiple therapy lines, including alkylating agents and immune modulators, which have been associated with secondary malignancies such as myelodysplastic syndrome (MDS). Anti-B-cell maturation antigen (BCMA) chimeric antigen receptor T cell (CART) therapy is efficacious in patients with relapsed/refractory (R/R) MM. However, the long-term complications, particularly MDS, are not well understood. Whether CART therapy causes or promotes MDS has not been thoroughly investigated. In this study, we explored the causal relationship between MDS and CART therapy. We retrospectively examined the prevalence of MDS-related morphological and mutational changes before and after administration of CART therapy in five patients. Among them, four developed MDS after CART therapy, while one had pre-existing MDS prior to CART. None of the four patients who developed post-CART MDS showed morphological MDS changes prior to CART therapy. However, all four patients exhibited molecular alterations associated with MDS in their pre-CART as well as post-CART therapy bone marrow. No new mutations were observed. Our findings provide initial evidence suggesting that anti-BCMA CART therapy in MM may promote expansion of pre-existing MDS clones rather than causing development of new clones.

Polarization in public attitudes toward end-of-life decisions in Israel - A cross-sectional study.

OBJECTIVES: End-of-life (EoL) processes are a complex socio-normative and ethical phenomenon. This study aimed to generate a database of public opinion in Israel concerning EoL processes and decisions and to identify differences in attitudes across subgroups in the population, particularly based on experience as a family caregiver of a dying patient. METHODS: This cross-sectional study was performed in late March 2022. The study utilized an online sample of 605 adults over the age of 50 including those who accompanied a loved one to their death in the last 3 years. Participants were requested to provide their opinions and attitudes on several aspects of EoL decisions, including truth-telling, medically assisted dying, EoL procedures, pre-death actions, and family caregivers' engagement. RESULTS: While only 27% and ∼30% of participants support artificial respiration or feeding (respectively) of terminally ill patients, 66% support analgesic treatment, even at the risk of shortening life. The data show an association between religiosity and agreement with life-extending procedures. For example, while 83% of seculars support medically assisted dying, only 59% and 26% of traditional and religious respondents support it. However, no statistically significant differences were observed in support of family involvement in EoL process in any sociodemographic variable. SIGNIFICANCE OF RESULTS: The results of this study suggest that the Israeli public is relatively polarized on several issues about EoL processes, specifically patient autonomy and medically assisted dying. Yet, at the same time, there is a consensus among the Israeli public about certain EoL elements, particularly the importance of family caregivers in the EoL decision-making process.

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.

Utility of Galactomannan Screening for Early Detection of Invasive Aspergillosis in High-Risk Hemato-Oncology Patients.

INTRODUCTION: Invasive aspergillosis (IA) affects mainly patients with hematological malignancies, and early diagnosis is crucial for timely treatment. Most diagnoses are based on clinical and mycological criteria, mostly galactomannan (GM) test in serum or bronchoalveolar fluid, which is performed in case of clinical suspicion or as routine screening in patients at high risk who are not receiving anti-mold prophylaxis, for early detection of IA. The aim of this study was to assess in a real-world setting the efficacy of biweekly serum GM screening for the early detection of IA. METHODS: A retrospective cohort that included 80 adult patients treated at the Hematology Department, Hadassah Medical Center, 2016-2020, with a diagnosis of IA. Clinical and laboratory data were collected from patients' medical files and the rate of GM-driven, GM-associated, and non-GM-associated IA was calculated. RESULTS: There were 58 patients with IA. The rate of GM-driven diagnosis was 6.9%, GM-associated diagnosis was 43.1%, and non-GM-associated diagnosis was 56.9%. The GM test as a screening tool had led to IA diagnosis in only 0.2% of screened serums with a number needed to screen in order to find 1 patient with IA of 490. CONCLUSION: Clinical suspicion outweighs GM screening as a tool for early diagnosis of IA. Nevertheless, GM has an important role as a diagnostic tool for IA.

Long-Term Results with Thiotepa-Containing Conditioning Regimens for Autologous Stem Cell Transplantation.

Autologous stem cell transplantation (ASCT) remains a cornerstone in the treatment of both Hodgkin lymphoma (HL) and various non-Hodgkin lymphoma (NHL) subtypes. BEAM (carmustine, etoposide, cytarabine, and melphalan) is the most frequently used conditioning regimen; however, owing due to limited availability and toxicity of carmustine, thiotepa-containing regimens have been suggested. We previously reported encouraging results in ASCT with a TECAM (thiotepa, etoposide, cyclophosphamide, cytarabine, and melphalan) conditioning regimen from 2000 to 2013. We aimed to update our experience with the TECAM regimen by adding our experience from 2013 to 2020 to the previously reported cohort. Moreover, we aimed to use the detailed data for the 2 transplant cohorts to identify improvements in ASCT outcomes in the recent era. We retrospectively analyzed all lymphoma patients who underwent ASCT at our center between January 2000 and December 2020. A total of 353 lymphoma patients were included (142 in the newer cohort added to 211 previously reported patients), all of whom were treated with our standard TECAM conditioning regimen. The cohort included 127 patients with HL, 107 with DLBCL, and 119 with other NHL subtypes. The newer cohort was characterized by significantly poorer Eastern Cooperative Oncology Group Performance Status (ECOG-PS) prior to ASCT (45.7% versus 19.3% with ECOG-PS ≥1; P < .01), whereas a higher proportion of patients entered transplantation in complete response (CR) (71.9% versus 47.8%; P < .01). The median follow-up after ASCT was 136.4 months (95% confidence interval [CI], 91.4 to 181.4 months). The 3-year progression-free survival (PFS) and overall survival (OS) rates post-ASCT for the entire cohort were 59.8% and 79.3%, respectively. Evaluating the 303 of 353 patients (86.4%) who entered ASCT with a responsive disease-a population that represents today's approach to the selection of patients for ASCT-the 3-year PFS and OS rates were 61.5% and 81.9%, respectively. In this population, the 3-year PFS rate was 62.2% for HL, 62.6% for DLBCL, 64.3% for primary central nervous system lymphoma (PCNSL), and the 3-year OS rate were 90.1%, 75.2%, and 78.6%, respectively. OS was significantly better in the newer cohort (P < .01), but not when evaluating only patients who entered ASCT with responsive disease. Dose reductions, poor disease status, and poor ECOG-PS at ASCT entry were associated with worse outcomes across all lymphoma subtypes. In accordance with our previous report, patients entering transplantation for DLBCL with a partial response achieved similar outcomes as those with a CR. Eighteen patients died within the first 100 days, 8 due to disease progression and 10 due to transplantation-related complications (2.8%). There were no cases of interstitial pneumonitis syndrome. Twenty-two cases (6.2%) of secondary malignancies were documented. Our results confirm that TECAM is an effective and safe conditioning regimen for ASCT in patients with HL and various NHLs, including favorable results in PCNSL. Despite a higher proportion of frail patients, the newer cohort's outcomes were favorable, driven by better lymphoma control pretransplantation. In the DLBCL cohort, ECOG-PS had more prognostic value than achieving a CR pre-ASCT, a finding relevant to the optimal allocation of patients to different treatment options in the era of chimeric antigen receptor T cell availability.

Interprofessional palliative and end-of-life education: short-term and long-term outcomes - mixed-methods analysis.

ObjectiveInterprofessional care is integral to end-of-life (EOL) and palliative care (PC) and may be suited for EOL and PC education.We evaluate the impact of an interprofessional EOL care curriculum on participants, during the course, on completion and 4 years laterusing quantitative (questionnaires) and qualitative (open-ended questions and interviews) methods.The course included 14 fifth and sixth-year medical students, 9 social work students and 7 nursing students enrolled in master's degree programmes. Seventeen participants completed questionnaires 4 years later and eight participated in interviews.On postcourse questionnaires, participants attributed high value to interprofessional education (IPE) (4.77/5±0.50 on a Likert scale). Four years later, participants reported that IPE impacted their professional (3.65/5±1.11) and personal lives (3.94/5±1.09) and found PC IPE important (4.88/5±0.33).Conventional content analysis showed that the course enabled discussion of death and dying and provided an opportunity for a personal-emotional journey. It offered an approach to EOL care and an opportunity to experience interprofessional teamwork at the EOL resulting in behavioural change.Interprofessional EOL education resulted in meaningful and lasting self-reported personal and professional behavioural outcomes.

Venetoclax-based salvage therapy for adult patients with relapsed/refractory acute lymphoblastic leukemia.

OBJECTIVES: Dysregulation of BCL-2 family members has been reported in acute lymphocytic leukemia (ALL), with various BH3-dependencies of the leukemic clone. We conducted a multicenter retrospective cohort of patients with relapsed/refractory B or T ALL, with ven-chemotherapy or ven-navitoclax combinations, to assess efficacy and safety. METHODS: Seventeen patients were included in the analysis, median age was 32 years, with 6 B-ALL and 11 T-ALL patients. Nine patients received venetoclax combined with chemotherapy, and 13 patients received venetoclax in combination with navitoclax, vincristine and asparaginase, of which 5 were already exposed to venetoclax in previous lines. RESULTS: ORR was 55% and 46% among the ven-chemotherapy and the ven-navitoclax-chemotherapy, respectively. Most of the responders proceeded to an allogenic bone marrow transplant in both cohorts. The most common adverse effects of the ven-navitoclax combination were infectious complications and hepatotoxicity. CONCLUSIONS: Our data demonstrated the possible efficacy of ven-chemotherapy and ven-navitoclax in r/r ALL with moderate toxicity.

Risk factors and outcomes of COVID-19 in adult patients with hematological malignancies: A single-center study showing lower than expected rates of hospitalization and mortality.

BACKGROUND: Studies addressing coronavirus disease 2019 (COVID-19) in patients with hematological malignancies have reported mortality rates of up to 40%; however, included predominantly hospitalized patients. METHODS: During the first year of the pandemic, we followed adult patients with hematological malignancies treated at a tertiary center in Jerusalem, Israel, who contracted COVID-19, with the aim of studying risk factors for adverse COVID-19-related outcomes. We used remote communication to track patients managed at home-isolation, and patient questioning to assess the source of COVID-19 infection, community versus nosocomial. RESULTS: Our series included 183 patients, median age was 62.5 years, 72% had at least one comorbidity and 39% were receiving active antineoplastic treatment. Hospitalization, critical COVID-19, and mortality rates were 32%, 12.6%, and 9.8%, respectively, remarkably lower than previously reported. Age, multiple comorbidities, and active antineoplastic treatment were significantly associated with hospitalization due to COVID-19. Treatment with monoclonal antibodies was strongly associated with both hospitalization and critical COVID-19. In older (≥60) patients not receiving active antineoplastic treatment, mortality, and severe COVID-19 rates were comparable to those of the general Israeli population. We did not detect patients that contracted COVID-19 within the Hematology Division. CONCLUSION: These findings are relevant for the future management of patients with hematological malignancies in COVID-19-affected regions.

Agencies Displayed by Patients, Medical Teams, and Caregivers at the End of Life from the Perspectives of Family Members - A Qualitative Study.

Background: End-of-life (EoL) Care is challenging for terminally-ill patients and their caregivers. This research is aimed to examine the relational agencies of the patients, the caregivers, and the medical teams in the context of EoL care, with a particular emphasis on the caregivers. Methods: This study is based on the qualitative analysis of interviews with 12 individuals who were closely supported a loved one to their death from a terminal illness. Results: Information collected revealed several agency-related themes. Family caregivers are significant entities in managing the 'case' of a seriously ill individual. At the final or more advanced stages of the EoL process, caregivers gradually shift from a supportive role to being active agents, but not always backed by the necessary experience, knowledge, or the requisite emotional resilience. Conclusions: Based on recognizing their agentic proactivity, a clear and elaborate articulation of the family caregivers' roles is needed.

Successful treatment with plasma exchange in life-threatening hyperhemolytic syndrome unrelated to sickle cell disease.

INTRODUCTION: Hyperhemolytic syndrome (HHS) is a severe form of delayed transfusion reaction primarily described in sickle cell anemia patients which is characterized by a hemoglobin decrease to pre-transfusion levels or lower, often with reticulocytopenia and no evidence of auto- or allo-antibodies. CASE PRESENTATION: We present two cases of severe HHS in patients without sickle cell anemia refractory to treatment with steroids, immunoglobulins, and rituximab. In one case, temporary relief was achieved with eculizumab. In both cases, plasma exchange resulted in a profound and immediate response allowing for splenectomy and resolution of hemolysis. DISCUSSION/CONCLUSION: We discuss the pathophysiology of HHS, its presentation and treatment and expand on the possible role of plasma exchange in this setting.

Development and manufacture of novel locally produced anti-BCMA CAR T cells for the treatment of relapsed/refractory multiple myeloma: results from a phase I clinical trial.

Anti-B-cell maturation antigen (BCMA) chimeric antigen receptor T-cell (CAR T) therapy shows remarkable efficacy in patients with relapsed and/or refractory (R/R) multiple myeloma (MM). HBI0101, a novel second generation optimized anti- BCMA CAR T-cell therapy, was developed in an academic setting. We conducted a phase I dose-escalation study of HBI0101 (cohort 1: 150x106 CAR T cells, n=6; cohort 2: 450x106 CAR T cells, n=7; cohort 3: 800x106 CAR T cells, n=7) in 20 heavily pre-treated R/R MM patients. Grade 1-2 cytokine release syndrome (CRS) was reported in 18 patients (90%). Neither grade 3-4 CRS nor neurotoxicity of any grade were observed. No dose-limiting toxicities were observed in any cohort. The overall response rate (ORR), (stringent) complete response (CR/sCR), and very good partial response rates were 75%, 50%, and 25%, respectively. Response rates were dose-dependent with 85% ORR, 71% CR, and 57% minimal residual disease negativity in the high-dose cohort 3. Across all cohorts, the median overall survival (OS) was 308 days (range 25-466+), with an estimated OS of 55% as of June 27th (data cut-off). The median progression-free survival was 160 days, with 6 subjects remaining progression free at the time of data cut-off. Our findings demonstrate the manageable safety profile and efficacy of HBI0101. These encouraging data support the decentralization of CAR T production in an academic setting, ensuring sufficient CAR T supply to satisfy the increasing local demand. Clinicaltrials.gov NCT04720313.

The Emerging Role of Venetoclax-Based Treatments in Acute Lymphoblastic Leukemia.

Venetoclax, a B-cell lymphoma (BCL-2) inhibitor, in combination with hypomethylating agents has become the new standard of care in elderly and unfit patients with acute myeloid leukemia, with significantly improved overall survival and quality of life. Studies of venetoclax combined with high-dose chemotherapy are emerging with evidence of higher rates of molecular remission. Recently, a growing number of publications bring forth the use of venetoclax in patients with acute lymphoblastic leukemia (ALL). In the current review, we present the biological rationale of BCL-2 inhibition in ALL, how the interplay of BH3 proteins modulate the response and the current clinical experience with various combinations.