Associations Between Family-Assessed Quality-of-Dying-and-Death Latent Classes and Bereavement Outcomes for Family Surrogates of ICU Decedents.

OBJECTIVES: To examine associations between family surrogates' bereavement outcomes and four previously determined quality of dying and death (QODD) latent classes (high, moderate, poor-to-uncertain, and worst). DESIGN: Prospective, longitudinal, observational study. SETTING: Medical ICUs at two academically affiliated medical centers in Taiwan. PATIENTS/PARTICIPANTS: Three hundred nine family surrogates responsible for decision-making for critically ill patients at high risk of death (Acute Physiology and Chronic Health Evaluation II scores > 20) from a disease. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Participants were assessed by the depression and anxiety subscales of the Hospital Anxiety and Depression Scale, the Impact of Event Scale-Revised, 11 items of the Prolonged Grief Disorder (PGD) scale, and the Medical Outcomes Study 36-Item Short-Form Health Survey at 1, 3, 6, 13, 18, and 24 months post-loss. We simultaneously examined associations of four QODD latent classes with physical and mental health-related quality of life (HRQOL) and symptoms of anxiety, depression, post-traumatic stress disorder (PTSD), and PGD assessed over 24 bereavement months using multivariate hierarchical linear modeling. Surrogates' distinct QODD latent classes assessed at 1-month post-loss were significantly associated with bereavement outcomes, except for physical HRQOL and PGD symptoms. Significantly more depressive symptoms and worse mental HRQOL (ß [95% CI]) were reported by bereaved surrogates in the moderate (1.958 [1.144-2.772], -2.245 [-3.961 to -0.529]), poor-to-uncertain (2.224 [1.438-3.010], -7.026 [-8.683 to -5.369]), and worst (2.081 [1.215-2.964], -4.268 [-6.096 to -2.440]) QODD classes than those in the high QODD class. Bereaved surrogates in the moderate (2.095 [1.392-2.798]) and poor-to-uncertain (0.801 [0.123-1.480]) QODD classes reported more anxiety symptoms, whereas those in the poor-to-uncertain QODD class suffered more PTSD symptoms (2.889 [1.005-4.774]) than those in the high QODD class. CONCLUSIONS: The four distinct QODD latent classes were significantly associated with ICU family surrogates' bereavement outcomes, suggesting targets to improve end-of-life care quality in ICUs.

Impact of previous S-1 treatment on efficacy of liposomal irinotecan plus 5-fluorouracil and leucovorin in patients with metastatic pancreatic cancer.

BACKGROUND/OBJECTIVES: Liposomal irinotecan plus 5-fluorouracil and leucovorin (nal-IRI + 5-FU/LV) provides survival benefits for metastatic pancreatic adenocarcinoma (mPDAC) refractory to gemcitabine-based treatment, mainly gemcitabine plus nab-paclitaxel (GA), in current practice. Gemcitabine plus S-1 (GS) is another commonly administered first-line regimen before nab-paclitaxel reimbursement; however, the efficacy and safety of nal-IRI + 5-FU/LV for mPDAC after failed GS treatment has not been reported and was therefore explored in this study. METHODS: In total, 177 patients with mPDAC received first-line GS or GA treatment, followed by second-line nal-IRI + 5-FU/LV treatment (identified from a multicenter retrospective cohort in Taiwan from 2018 to 2020); 85 and 92 patients were allocated to the GS and GA groups, respectively. Overall survival (OS), time-to-treatment failure (TTF), and adverse events were compared between the two groups. RESULTS: The baseline characteristics of the two groups were generally similar; however, a higher median age (67 versus 62 years, p < 0.001) and fewer liver metastases (52% versus 78%, p < 0.001) were observed in the GS versus GA group. The median OS was 15.0 and 15.9 months in the GS and GA groups, respectively (p = 0.58). The TTF (3.1 versus 2.8 months, p = 0.36) and OS (7.6 versus 6.7 months, p = 0.83) after nal-IRI treatment were similar between the two groups. More patients in the GS group developed mucositis during nal-IRI treatment (15% versus 4%, p = 0.02). CONCLUSIONS: The efficacy of second-line nal-IRI +5-FU/LV treatment was unaffected by prior S-1 exposure. GS followed by nal-IRI treatment is an alternative treatment sequence for patients with mPDAC.

Serum Cytokines Correlate with Pretreatment Body Mass Index-adjusted Body Weight Loss Grading and Cancer Progression in Patients with Stage III Esophageal Squamous Cell Carcinoma Undergoing Neoadjuvant Chemoradiotherapy Followed by Surgery.

Serum Cytokines Correlate with Pretreatment Body Mass Index-Adjusted Body Weight Loss Grading and Cancer Progression in Patients with Stage III Esophageal Squamous Cell Carcinoma Undergoing Neoadjuvant Chemoradiotherapy Followed by Surgery. Circulating cytokines have been linked to the development of esophageal squamous cell carcinoma (ESCC) and its associated malnutrition process. Nonetheless, given the varied disease stages and treatment modalities in previous studies, the clinical relevance of their findings is limited. We retrospectively studied 52 patients with stage III ESCC who underwent neoadjuvant chemoradiotherapy and curative-intent surgery. We investigated the association of clinicopathological features, pretreatment laboratory data, and pretreatment inflammatory status, as indicated by the levels of albumin, C-reactive protein, and 10 circulating cytokines, namely tumor necrosis factor-alpha (TNF-α), interferon-gamma, interleukin-1-beta (IL-1ß), IL-4, IL-6, IL-8, IL-12, IL-13, IL-17A, and IL-23, with malnutrition, as shown by body mass index-adjusted body weight loss (BMI-BWL) grading, cancer progression. Half the patients showed severe malnutrition and high BMI-BWL grades (3 and 4). Multivariate analysis revealed an independent association between the levels of three cytokines (TNF-α, ≤ 5.8 pg/ml; IL-1ß, > 0.4 pg/ml; IL-6, ≤ 12.4 pg/ml) and high BMI-BWL grades and between IL-4 levels > 22.5 pg/ml and cancer progression. All 10 cytokines were closely correlated with each other. In conclusion, TNF-α, IL-1ß, and IL-6 were independent markers of malnutrition status and IL-4 was a prognostic factor for cancer progression in this patient population.

Frailty is an independent factor for health-related quality of life in patients with head and neck cancer receiving definitive concurrent chemoradiotherapy.

PURPOSE: Health-related quality of life (HRQoL) is associated with treatment-related complications and poor survival in patients with head and neck cancer (HNC). We investigated the effects of frailty on HRQoL in patients with HNC receiving definitive concurrent chemoradiotherapy (CCRT). METHODS: A total of 461 consecutive patients with locally advanced HNC who received CCRT between 2017 and 2018 at three medical centers in Taiwan were included. Frailty and HRQoL were assessed using the Comprehensive Geriatric Assessment and QLQ-H&N35 before CCRT. The sum score was calculated based on the first 30 questions of QLQ-H&N35. Multivariate analysis was performed to evaluate the impact of frailty on HRQoL. RESULTS: The overall sum score was 39 (34-49). The sum scores of patients with impairments in 0, 1, 2, 3, and ≥ 4 frailty domains were 34 (32-38), 40 (34-47), 46 (36-55), 48 (41-64), and 56 (50-60), respectively. Patients with impairments in more frailty domains had a higher symptom burden (p for trend < 0.001). Frail patients tended to experience symptoms across all QLQ-H&N35 subscales. Sex, body mass index, tumor type, tumor stage, Eastern Cooperative Oncology Group performance status, and frailty were determinants of HRQoL in the univariate analysis. Frailty was an independent determinant of HRQoL in the multivariate analysis. CONCLUSION: Routine frailty assessment may serve as a surrogate for the selection of patients with HNC with poor HRQoL before CCRT. Further studies are needed to determine whether appropriate interventions in frail patients would improve their HRQoL during CCRT.

Impact of preoperative frailty on the surgical and survival outcomes in older patients with solid cancer after elective abdominal surgery.

BACKGROUND: Frailty is common in older patients with cancer; however, its clinical impact on the survival outcomes has seldom been examined in these patients. This study aimed to investigate the association of frailty with the survival outcomes and surgical complications in older patients with cancer after elective abdominal surgery in Taiwan. METHODS: We prospectively enrolled 345 consecutive patients aged ≥65 years with newly diagnosed cancer who underwent elective abdominal surgery between 2016 and 2018. They were allocated into the fit, pre-frail, and frail groups according to comprehensive geriatric assessment (CGA) findings. RESULTS: The fit, pre-frail, and frail groups comprised 62 (18.0%), 181 (52.5%), and 102 (29.5%) patients, respectively. After a median follow-up of 48 (interquartile range, 40-53) months, the mortality rates were 12.9%, 31.5%, and 43.1%, respectively. The adjusted hazard ratio was 1.57 (95% confidence interval [CI], 0.73-3.39; p = 0.25) and 2.87 (95% CI, 1.10-5.35; p = 0.028) when the pre-frail and frail groups were compared with the fit group, respectively. The frail group had a significantly increased risk for a prolonged hospital stay (adjusted odds ratio, 2.22; 95% CI, 1.05-4.69; p = 0.022) compared with the fit group. CONCLUSION: Pretreatment frailty was significantly associated with worse survival outcomes and more surgical complications, with prolonged hospital stay, in the older patients with cancer after elective abdominal surgery. Preoperative frailty assessment can assist physicians in identifying patients at a high risk for surgical complications and predicting the survival outcomes of older patients with cancer.

Impact of pretreatment quality of life on tolerance and survival outcome in head and neck cancer patients undergoing definitive CCRT.

BACKGROUND: Health-related quality of life (HRQoL) is a predictor of treatment outcomes in cancer patients. This study aimed to evaluate the effect of pretreatment HRQoL on treatment tolerance and survival outcomes in patients with HNC planned for concurrent chemoradiotherapy (CCRT) in Taiwan. METHODS: This study included 461 patients with HNC planned for definitive CCRT at three medical centers in Taiwan between August 2017 and December 2018. HRQoL was assessed using the QLQ-HN35 one week before the initiation of CCRT. Patients were grouped based on the sum scores of QLQ-HN35 (

Factors of preparedness for loss from cancer among Taiwanese family caregivers.

This cohort study investigated factors associated with 336 Taiwanese family caregivers' emotional and cognitive preparedness for death of a loved one with terminal cancer. Caregivers' death-preparedness states (no-death-preparedness [as reference], cognitive-death-preparedness-only, emotional-death-preparedness-only, and sufficient-death-preparedness states) were previously identified. Associations of factors with these states were determined by a hierarchical generalized linear model. Financial hardship decreased caregivers' likelihood for the emotional-death-preparedness-only and sufficient-death-preparedness states. Physician prognostic disclosure increased membership in the cognitive-death-preparedness-only and sufficient-death-preparedness states. The better the quality of the patient-caregiver relationship, the higher the odds for the emotional-death-preparedness-only and sufficient-death-preparedness states, whereas the greater the tendency for caregivers to communicate end-of-life issues with their loved one, the lower the odds for emotional-death-preparedness-only state membership. Stronger coping capacity increased membership in the emotional-death-preparedness-only state, but perceived social support was not associated with state membership. Providing effective interventions tailored to at-risk family caregivers' specific needs may facilitate their death preparedness.

Clinical characteristics and genetic HLA marker for patients with oxaliplatin-induced adverse drug reactions.

BACKGROUND: Oxaliplatin is commonly used to treat gastrointestinal malignancies. However, its applications are limited due to potential adverse drug reactions (ADRs), particularly severe anaphylactic shock. There is no method to predict or prevent ADRs caused by oxaliplatin. Therefore, we aimed to investigate the genetic HLA predisposition and immune mechanism of oxaliplatin-induced ADRs. METHODS: A retrospective review was performed for 154 patients with ADRs induced by oxaliplatin during 2016-2021 recorded in our ADR notification system. HLA genotyping was conducted for 47 patients with oxaliplatin-induced ADRs, 1100 general population controls, and 34 oxaliplatin-tolerant controls in 2019-2023. The in vitro basophil activation test (BAT) was performed and oxaliplatin-specific IgE levels were determined. RESULTS: The incidence of oxaliplatin-induced ADRs and anaphylactic shock in our cohort was 7.1% and 0.15%, respectively. Of the 154 patients, 67.5% suffered rash/eruption; 26.0% of the patients who could not undergo oxaliplatin rechallenge were considered to show oxaliplatin-induced immune-mediated hypersensitivity reactions (HRs). The genetic study found that the HLA-DRB∗12:01 allele was associated with oxaliplatin-induced HRs compared to the general population controls (sensitivity = 42.9%; odds ratio [OR] = 3.4; 95% CI = 1.4-8.2; P = 0.008) and tolerant controls (OR = 12; 95% CI = 2.3-63.7; P = 0.001). The in vitro BAT showed higher activation of CD63+ basophils in patients with oxaliplatin-induced HRs compared to the tolerant controls (P < 0.05). Only four patients (8.5%) with oxaliplatin-induced ADRs were positive for oxaliplatin-specific IgE. CONCLUSIONS: This study found that 26.0% of patients with oxaliplatin-induced ADRs could not undergo oxaliplatin rechallenge. HLA-DRB∗12:01 is regarded as a genetic marker for oxaliplatin-induced hypersensitivity.

ICU Bereaved Surrogates' Transition Through States of Co-Occurring Prolonged Grief Disorder, Posttraumatic Stress Disorder, and Depression Symptoms.

OBJECTIVES: Grief-related psychological distress often co-occurs to conjointly impair function during bereavement. Knowledge of comorbid grief-related psychological distress is limited: no longitudinal study has examined dynamic patterns of co-occurring prolonged grief disorder (PGD), posttraumatic stress disorder (PTSD), and depression, and previous assessment time frames have been variable and potentially inadequate given the duration criterion for PGD. Therefore, the purpose of this study was to investigate the transition of distinct symptom states based on the co-occurrence of PGD, PTSD, and depression symptoms for ICU bereaved surrogates over their first two bereavement years. DESIGN: Prospective, longitudinal, observational study. SETTING: Medical ICUs at two academically affiliated medical centers in Taiwan. PATIENTS/PARTICIPANTS: Three hundred three family surrogates responsible for decision-making for critically ill patients at high risk of death (Acute Physiology and Chronic Evaluation II scores > 20) from a disease. INTERVENTION: None. MEASUREMENTS AND MAIN RESULTS: Participants were assessed by 11 items of the Prolonged Grief Disorder (PG-13) scale, the Impact of Event Scale-Revised, and the depression subscale of the Hospital Anxiety and Depression Scale at 6, 13, 18, and 24 months postloss. PGD-PTSD-depression-symptom states and their evolution were examined by latent transition analysis. The following four distinct PGD-PTSD-depression-symptom states (prevalence) were initially identified: resilient (62.3%), subthreshold depression-dominant (19.9%), PGD-dominant (12.9%), and PGD-PTSD-depression comorbid (4.9%) states. These PGD-PTSD-depression-symptom states remained highly stable during the first two bereavement years, with transitions predominantly toward resilience. Prevalence for each state at 24 months postloss was 82.1%, 11.4%, 4.0%, and 2.5%, respectively. CONCLUSIONS: Four highly stable PGD-PTSD-depression-symptom states were identified, highlighting the importance of screening for subgroups of ICU bereaved surrogates with increased PGD or comorbid PGD, PTSD, and depression symptoms during early bereavement.

A novel computational framework for genome-scale alternative transcription units prediction.

Alternative transcription units (ATUs) are dynamically encoded under different conditions and display overlapping patterns (sharing one or more genes) under a specific condition in bacterial genomes. Genome-scale identification of ATUs is essential for studying the emergence of human diseases caused by bacterial organisms. However, it is unrealistic to identify all ATUs using experimental techniques because of the complexity and dynamic nature of ATUs. Here, we present the first-of-its-kind computational framework, named SeqATU, for genome-scale ATU prediction based on next-generation RNA-Seq data. The framework utilizes a convex quadratic programming model to seek an optimum expression combination of all of the to-be-identified ATUs. The predicted ATUs in Escherichia coli reached a precision of 0.77/0.74 and a recall of 0.75/0.76 in the two RNA-Sequencing datasets compared with the benchmarked ATUs from third-generation RNA-Seq data. In addition, the proportion of 5'- or 3'-end genes of the predicted ATUs, having documented transcription factor binding sites and transcription termination sites, was three times greater than that of no 5'- or 3'-end genes. We further evaluated the predicted ATUs by Gene Ontology and Kyoto Encyclopedia of Genes and Genomes functional enrichment analyses. The results suggested that gene pairs frequently encoded in the same ATUs are more functionally related than those that can belong to two distinct ATUs. Overall, these results demonstrated the high reliability of predicted ATUs. We expect that the new insights derived by SeqATU will not only improve the understanding of the transcription mechanism of bacteria but also guide the reconstruction of a genome-scale transcriptional regulatory network.

Associations Between Surrogates' Decisional Regret Trajectories and Bereavement Outcomes.

BACKGROUND: Family surrogates experience heterogeneous decisional regret and negative long-lasting postdecision impacts. Cross-sectional findings on the associations between decisional regret and surrogates' bereavement outcomes are conflicting and cannot illustrate the directional and dynamic evolution of these associations. In this study, we sought to longitudinally examine the associations between 4 previously identified decisional-regret trajectories and bereavement outcomes among family surrogates of terminally ill patients with cancer. PATIENTS AND METHODS: This prospective, longitudinal, observational study included 377 family surrogates. Decisional regret was measured using the 5-item Decision Regret Scale, and 4 decisional regret trajectories were identified: resilient, delayed-recovery, late-emerging, and increasing-prolonged. Associations between bereavement outcomes (depressive symptoms, prolonged grief symptoms, and physical and mental health-related quality of life [HRQoL]) and decisional-regret trajectories were examined simultaneously by multivariate hierarchical linear modeling using the resilient trajectory as a reference. RESULTS: Surrogates in the delayed-recovery, late-emerging, and increasing-prolonged trajectories experienced significantly higher symptoms of prolonged grief (ß [95% CI], 1.815 [0.782 to 2.848]; 2.312 [0.834 to 3.790]; and 7.806 [2.681 to 12.931], respectively) and poorer physical HRQoL (-1.615 [-2.844 to -0.386]; -1.634 [-3.226 to -0.042]; and -4.749 [-9.380 to -0.118], respectively) compared with those in the resilient trajectory. Membership in the late-emerging and increasing-prolonged trajectories was associated with higher symptoms of depression (ß [95% CI], 2.942 [1.045 to 4.839] and 8.766 [2.864 to 14.668], respectively), whereas only surrogates in the increasing-prolonged decisional-regret trajectory reported significantly worse mental HRQoL (-4.823 [-8.216 to -1.430]) than those in the resilient trajectory. CONCLUSIONS: Surrogates who experienced delayed-recovery, unresolved, or late-emerging decisional regret may carry ceaseless doubt, guilt, or self-blame for patient suffering, leading to profound symptoms of prolonged grief, depressive symptoms, and worse HRQoL over their first 2 bereavement years.

Associations of prognostic-awareness-transition patterns with emotional distress and quality of life during terminally ill cancer patients' last 6 months of life.

OBJECTIVE: Unprecedently investigate associations of prognostic-awareness-transition patterns with (changes in) depressive symptoms, anxiety symptoms, and quality of life (QOL) during cancer patients' last 6 months. METHODS: In this secondary analysis study, 334 cancer patients in their last 6 months transitioned between four prognostic-awareness states (unknown and not wanting to know, unknown but wanting to know, inaccurate awareness, and accurate awareness), thus constituting three transition patterns: maintaining-accurate-, gaining-accurate-, and maintaining-inaccurate/unknown prognostic awareness. A multivariate hierarchical linear model evaluated associations of the transition patterns with depressive symptoms, anxiety symptoms, and QOL determined at final assessment and by mean difference between the first and last assessment. RESULTS: At the last assessment before death, the gaining-accurate-prognostic-awareness group reported higher levels of depressive symptoms (estimate [95% confidence interval] = 1.59 [0.35-2.84]) and the maintaining- and gaining-accurate-prognostic-awareness groups suffered more anxiety symptoms (1.50 [0.44-2.56]; 1.42 [0.13-2.71], respectively) and poorer QOL (-7.07 [-12.61 to 1.54]; -11.06 [-17.76 to -4.35], respectively) than the maintaining-inaccurate/unknown-prognostic-awareness group. Between the first and last assessment, the maintaining- and gaining-accurate-prognostic-awareness groups' depressive symptoms (1.59 [0.33-2.85]; 3.30 [1.78-4.82], respectively) and QOL (-5.04 [-9.89 to -0.19]; -8.86 [-14.74 to -2.98], respectively) worsened more than the maintaining-inaccurate/unknown-prognostic-awareness group, and the gaining-accurate-prognostic-awareness group's depressive symptoms increased more than the maintaining-accurate-prognostic-awareness group (1.71 [0.42-3.00]). CONCLUSIONS: Unexpectedly, patients who maintained/gained accurate prognostic awareness suffered more depression, anxiety, and poorer QOL at end of life. Promoting accurate prognostic awareness earlier in the terminal-cancer trajectory should be supplemented with adequate psychological care to alleviate patients' emotional distress and enhance QOL. TRIAL REGISTRATION: ClinicalTrials.gov:NCT01912846.

Factors associated with cancer patients' distinct death-preparedness states.

BACKGROUND/OBJECTIVE: Facilitating death preparedness is important for improving cancer patients' quality of death and dying. We aimed to identify factors associated with the four death-preparedness states (no-preparedness, cognitive-only, emotional-only, and sufficient-preparedness) focusing on modifiable factors. METHODS: In this cohort study, we identified factors associated with 314 Taiwanese cancer patients' death-preparedness states from time-invariant socio-demographics and lagged time-varying modifiable variables, including disease burden, physician prognostic disclosure, patient-family communication on end-of-life (EOL) issues, and perceived social support using hierarchical generalized linear modeling. RESULTS: Patients who were male, older, without financial hardship to make ends meet, and suffered lower symptom distress were more likely to be in the emotional-only and sufficient-preparedness states than the no-death-preparedness-state. Younger age (adjusted odds ratio [95% confidence interval] = 0.95 [0.91, 0.99] per year increase in age) and greater functional dependency (1.05 [1.00, 1.11]) were associated with being in the cognitive-only state. Physician prognostic disclosure increased the likelihood of being in the cognitive-only (51.51 [14.01, 189.36]) and sufficient-preparedness (47.42 [10.93, 205.79]) states, whereas higher patient-family communication on EOL issues reduced likelihood for the emotional-only state (0.38 [0.21, 0.69]). Higher perceived social support reduced the likelihood of cognitive-only (0.94 [0.91, 0.98]) but increased the chance of emotional-only (1.09 [1.05, 1.14]) state membership. CONCLUSIONS: Death-preparedness states are associated with patients' socio-demographics, disease burden, physician prognostic disclosure, patient-family communication on EOL issues, and perceived social support. Providing accurate prognostic disclosure, adequately managing symptom distress, supporting those with higher functional dependence, promoting empathetic patient-family communication on EOL issues, and enhancing perceived social support may facilitate death preparedness.

Effect of prophylactic tube feeding in head and neck cancer patients with high Mallampati score undergoing definitive concurrent chemoradiotherapy.

PURPOSE: There is no consensus on the selection of appropriate prophylactic tube feeding in patients with head and neck squamous cell carcinoma (HNSCC) undergoing concurrent chemoradiotherapy (CCRT). This study aimed to evaluate the effect of prophylactic tube feeding in patients with HNSCC who presented with a high Mallampati score and underwent CCRT. METHODS: We prospectively enrolled 185 consecutive patients with stage II to IVa HNSCC and a pre-treatment Mallampati score of 3 or 4 who received CCRT between August 2017 and December 2018 with follow-up data collected retrospectively. Patients were divided to either with or without prophylactic tube feeding group for comparison of treatment tolerance, toxicities, and quality of life(QOL). Propensity score matching (PSM) was used to achieve balanced covariates across the two groups. RESULTS: Of the cohort, 52 (28.1%) and 133 (71.9%) patients were allocated to the prophylactic and non-prophylactic tube feeding groups, respectively. Before and after PSM, patients in the tube feeding group had a significantly lower incidence of incomplete radiotherapy, incompletion of chemotherapy, emergency room visits, and grade 3 or higher infection, and improved symptoms of quality of life after CCRT than those in the non-tube feeding group. CONCLUSION: Prophylactic tube feeding was associated with better treatment tolerance, safety profiles, and quality of life in patients with HNSCC and high Mallampati scores who underwent CCRT. Therefore, Mallampati score might serve as a clinical tool for proactive selection of patients receiving prophylactic tube feeding in HNSCC patients upon receiving CCRT.

Temporal reciprocal relationships among anxiety, depression, and posttraumatic stress disorder for family surrogates from intensive care units over their first two bereavement years.

BACKGROUND/OBJECTIVE: Bereaved family surrogates from intensive care units (ICU) are at risk of comorbid anxiety, depression, and post-traumatic stress disorder (PTSD), but the temporal reciprocal relationships among them have only been examined once among veterans. This study aimed to longitudinally investigate these never-before-examined temporal reciprocal relationships for ICU family members over their first two bereavement years. METHODS: In this prospective, longitudinal, observational study, symptoms of anxiety, depression, and PTSD were assessed among 321 family surrogates of ICU decedents from 2 academically affiliated hospitals in Taiwan by the anxiety and depression subscales of the Hospital Anxiety and Depression Scale, and the Impact of Event Scale-Revised, respectively at 1, 3, 6, 13, 18, and 24 months postloss. Cross-lagged panel modeling was conducted to longitudinally examine the temporal reciprocal relationships among anxiety, depression, and PTSD. RESULTS: Examined psychological-distress levels were markedly stable over the first 2 bereavement years: autoregressive coefficients for symptoms of anxiety, depression, and PTSD were 0.585-0.770, 0.546-0.780, and 0.440-0.780, respectively. Cross-lag coefficients showed depressive symptoms predicted PTSD symptoms in the first bereavement year, whereas PTSD symptoms predicted depressive symptoms in the second bereavement year. Anxiety symptoms predicted symptoms of depression and PTSD at 13 and 24 months postloss, whereas depressive symptoms predicted anxiety symptoms at 3 and 6 months postloss while PTSD symptoms predicted anxiety symptoms during the second bereavement year. CONCLUSIONS: Different patterns of temporal relationships among symptoms of anxiety, depression, and PTSD over the first 2 bereavement years present important opportunities to target symptoms of specific psychological distress at different points during bereavement to prevent the onset, exacerbation, or maintenance of subsequent psychological distress.

Clinical Significance of Frailty on Treatment Outcome in Nongeriatric Patients With Head and Neck Cancer and Esophageal Cancer Undergoing Curative-Intent Concurrent Chemoradiotherapy.

BACKGROUND: Whether the prevalence of frailty and its clinical significance are relevant to treatment outcomes in younger (aged < 65 years) cancer patients remains uncertain. This study aimed to evaluate the impact of frailty on treatment outcomes in younger cancer patients with head and neck and esophageal malignancy. MATERIAL AND METHODS: This multicenter prospective study recruited 502 patients with locally advanced head and neck and esophageal cancer during 2016-2017 in Taiwan, aged 20-64 years who received curative-intent concurrent chemoradiotherapy (CCRT) as first-line antitumor treatment. Baseline frailty assessment using geriatric assessment (GA) was performed for each patient within 7 days before CCRT initiation. RESULTS: Frailty was observed in 169 (33.7%) of 502 middle-aged patients. Frail patients had significantly higher incidences of chemotherapy incompletion (16.6% versus 3.3%, P < .001) and radiotherapy incompletion (16.6% versus 3.6%, P < .001) than fit patients. During CCRT, frail patients had a significantly higher percentage of hospitalizations (42.0% versus 24.6%, P < .001) and a trend toward a higher percentage of emergency room visits (37.9% versus 30.0%, P = .08) than fit patients. Frail patients more likely had a significantly higher incidence of grade ≥ 3 adverse events than fit patients during CCRT. The 1-year survival rate was 68.7% and 85.2% (hazard ratio 2.56, 95% confidence interval 1.80-3.63, P < .001) for frail and fit patients, respectively. CONCLUSIONS: This study demonstrated the significance of pretreatment frailty on treatment tolerance, treatment-related toxicity, and survival outcome in younger patients with head and neck and esophageal cancer undergoing CCRT. While GA is commonly targeted toward the older population, frailty assessment by GA may also be utilized in younger patients for decision-making guidance and prognosis prediction.

Prolonged grief disorder and depression are distinguishable syndromes: A latent transition analysis for bereaved family caregivers of cancer patients.

OBJECTIVE: To determine whether distinctive prolonged-grief-disorder- (PGD) and depressive-symptom states emerge among family caregivers of cancer patients over their first 2 years of bereavement. This may extend cross-sectional evidence that PGD and major depressive disorder (MDD) symptoms can co-occur/occur independently and validate their construct distinctiveness. METHODS: In this secondary-analysis study, PGD symptoms and depressive symptoms were measured over 666 caregivers using 11 grief symptom items of the Prolonged Grief-13 scale and 16 items of the Center for Epidemiologic Studies-Depression scale, respectively. Distinct PGD/depressive-symptom states were identified by latent transition analysis with dichotomous indicators (presence/absence) of PGD or depressive symptoms. RESULTS: Four distinct PGD/depressive-symptom states emerged. The resilient and subthreshold depression-dominant states showed low and moderate probabilities of the presence of majority of depressive symptoms, respectively, with no PGD symptoms having a greater than moderate probability of presence. The depression-dominant state was marked by a high probability of the presence for 9 of 16 depressive symptoms, with moderate probabilities for almost all PGD symptoms. The PGD-depression comorbid state was characterized by a high probability of presence of all PGD symptoms and depressive symptoms, except for moderate probabilities of presence of two depressive symptoms. CONCLUSION: Our longitudinal identification of a predominantly depressive state but absence of a PGD-dominant state provides further evidence that PGD and MDD are related but distinct constructs that can occur independently or concurrently as the PGD-depression comorbid state. When PGD is suspected, bereaved individuals should be assessed for the potential comorbidity of MDD.

Associations of surrogates' death-preparedness states with decisional conflict and heightened decisional regret over cancer patients' last 6 months of life.

OBJECTIVE: Preparing family surrogates for patient death and end-of-life (EOL) decision making may reduce surrogate decisional conflict and regret. Preparedness for patient death involves cognitive and emotional preparedness. We assessed the associations of surrogates' death-preparedness states (that integrate both cognitive and emotional preparedness for patient death) with surrogates' decisional conflict and regret. METHODS: Associations of 173 surrogates' death-preparedness states (no, cognitive-only, emotional-only, and sufficient preparedness states) with decisional conflict (measured by the Decision Conflict Scale) and heightened decisional regret (Decision Regret Scale scores >25) were evaluated using hierarchical linear modeling and hierarchical generalized linear modeling, respectively, during a longitudinal observational study at a medical center over cancer patients' last 6 months. RESULTS: Surrogates reported high decisional conflict (mean [standard deviation] = 41.48 [6.05]), and 52.7% of assessments exceeded the threshold for heightened decisional regret. Surrogates in the cognitive-only preparedness state reported a significantly higher level of decisional conflict (ß = 3.010 [95% CI = 1.124, 4.896]) than those in the sufficient preparedness state. Surrogates in the no (adjusted odds ratio [AOR] [95% CI] = 0.293 [0.113, 0.733]) and emotional-only (AOR [95% CI] = 0.359 [0.149, 0.866]) preparedness states were less likely to suffer heightened decisional regret than those in the sufficient preparedness state. CONCLUSIONS: Surrogates' decisional conflict and heightened decisional regret are associated with their death-preparedness states. Improving emotional preparedness for the patient's death among surrogates in the cognitive-only preparedness state and meeting the specific needs of those in the no, emotional-only, and sufficient preparedness states are actionable high-quality EOL-care interventions that may lessen decisional conflict and decisional regret.

Associations of death-preparedness states with bereavement outcomes for family caregivers of terminally ill cancer patients.

OBJECTIVE: Death preparedness involves cognitive prognostic awareness and emotional acceptance of a relative's death. Effects of retrospectively assessed cognitive prognostic awareness and emotional preparedness for patient death have been individually investigated among bereaved family caregivers. We aimed to prospectively examine associations of caregivers' death-preparedness states, determined by conjoint cognitive prognostic awareness and emotional preparedness for death, with bereavement outcomes. METHODS: Associations of caregivers' death-preparedness states (no-death-preparedness, cognitive-death-preparedness-only, emotional-death-preparedness-only, and sufficient-death-preparedness states) at last preloss assessment with bereavement outcomes over the first two bereavement years were evaluated among 332 caregivers of advanced cancer patients using hierarchical linear models with the logit-transformed posterior probability for each death-preparedness state. RESULTS: Caregivers with a higher logit-transformed posterior probability for sufficient death-preparedness state reported less prolonged-grief symptoms, lower likelihoods of severe depressive symptoms and heightened decisional regret, and better mental health-related quality of life (HRQOL). Caregivers with a higher logit-transformed posterior probability for no-death-preparedness state reported less prolonged-grief symptoms, a lower likelihood of severe depressive symptoms, and better mental HRQOL. A higher logit-transformed posterior probability for cognitive-death-preparedness-only state was associated with bereaved caregivers' higher likelihood of heightened decisional regret, whereas that for emotional-death-preparedness-only state was not associated with caregivers' bereavement outcomes. CONCLUSIONS: Caregivers' bereavement outcomes were associated with their preloss death-preparedness states, except for physical health-related QOL. Interventions focused on not only cultivating caregivers' accurate prognostic awareness but also adequately preparing them emotionally for their relative's forthcoming death are actionable opportunities for high-quality end-of-life care and are urgently warranted to facilitate caregivers' bereavement adjustment.

ICU bereaved surrogates' comorbid psychological-distress states and their associations with prolonged grief disorder.

BACKGROUND/OBJECTIVE: Bereaved ICU family surrogates' psychological distress, e.g., anxiety, depression, and post-traumatic stress disorder (PTSD), is usually examined independently, despite the well-recognized comorbidity of these symptoms. Furthermore, the few studies exploring impact of psychological distress on development of prolonged grief disorder (PGD) did not consider the dynamic impact of symptom evolution. We identified surrogates' distinct patterns/states of comorbid psychological distress and their evolution over the first 3 months of bereavement and evaluated their associations with PGD at 6-month postloss. METHODS: A longitudinal observational study was conducted on 319 bereaved surrogates. Symptoms of anxiety, depression, PTSD, and PGD were measured by the anxiety and depression subscales of the Hospital Anxiety and Depression Scale, Impact of Event Scale-Revised scale, and the PGD-13, respectively. Distinct psychological-distress states and their evolution were examined by latent transition analysis. Association between psychological-distress states and PGD symptoms was examined by logistic regression. RESULTS: Three distinct comorbid psychological-distress states (prevalence) were initially identified: no distress (56.3%), severe-depressive/borderline-anxiety distress (30.5%), and severe-anxiety/depressive/PTSD distress (13.3%). Except for those in the stable no-distress state, surrogates tended to regress to states of less psychological distress at the subsequent assessment. The proportion of participants in each psychological-distress state changed to no distress (76.8%), severe-depressive/borderline-anxiety distress (18.6%), and severe-anxiety/depressive/PTSD distress (4.6%) at 3-month postloss. Surrogates in the severe-depressive/borderline-anxiety distress and severe-anxiety/depressive/PTSD-distress state at 3-month postloss were more likely to develop PGD at 6-month postloss (OR [95%] = 14.58 [1.48, 143.54] and 104.50 [10.45, 1044.66], respectively). CONCLUSIONS: A minority of family surrogates of ICU decedents suffered comorbid severe-depressive/borderline-anxiety distress and severe-anxiety/depressive/PTSD symptoms during early bereavement, but they were more likely to progress into PGD at 6-month postloss.