Concurrent Atezolizumab Plus Bevacizumab and High-Dose External Beam Radiotherapy for Highly Advanced Hepatocellular Carcinoma.

BACKGROUND: Atezolizumab plus bevacizumab (atezo-bev) has been recommended for advanced hepatocellular carcinoma (HCC). High-dose external beam radiotherapy (RT) is recognized for its excellent local tumor control. The efficacy and safety of concurrent atezo-bev with RT for highly advanced HCC has been minimally explored. METHODS: In this preliminary retrospective study, we assessed patients with highly advanced HCC, characterized by Vp4 portal vein thrombosis or tumors exceeding 50% of liver volume, who received concurrent atezo-bev and RT (group A). Group A included 13 patients who received proton radiation at a dose of 72.6 GyE in 22 fractions, and one patient who received photon radiation at a dose of 54 Gy in 18 fractions. This group was compared with 34 similar patients treated atezo-bev alone as a control (group B). The primary objectives were to evaluate the objective response rate (ORR), overall survival (OS), and safety. RESULTS: Baseline characteristics were similar between groups, except for a higher incidence of Vp4 portal vein thrombosis in group A (78.6% vs. 21.4%, P = .05). Group A achieved a higher ORR (50.0% vs. 11.8%, P < .01) and a longer OS (not reached vs. 5.5 months, P = .01) after a median follow-up of 5.2 months. Multivariate analysis indicated that concurrent RT independently favored longer OS (hazard ratio: 0.18; 95% CI, 0.05-0.63, P < .01). Group A did not increase any grade adverse events (78.6% vs. 58.8%, P = .19) or severe adverse events of grade ≥ 3 (14.3% vs. 14.7%, P = .97) compared to group B. CONCLUSIONS: The concurrent high-dose external beam radiotherapy appears to safely enhance the effectiveness of atezolizumab plus bevacizumab for highly advanced patients with HCC. Further studies are warranted to confirm these findings.

Prophylactic Versus Reactive Megestrol Acetate Use for Critical Body Weight Loss in Patients with Pharyngeal and Laryngeal Squamous Cell Carcinoma Undergoing Concurrent Chemoradiotherapy.

This study compared the effects of megestrol acetate (MA) prophylactic (p-MA) versus reactive (r-MA) use for critical body-weight loss (>5% from baseline) during concurrent chemoradiotherapy (CCRT) in patients with advanced pharyngolaryngeal squamous cell carcinoma (PLSCC).Patients receiving CCRT alone in two phase-II trials were included for analyses. Both the p-MA and r-MA cohorts received the same treatment protocol at the same institution, and the critical body-weight loss, survival, and adverse event profiles were compared.The mean (SD) weight loss was 5.1% (4.7%) in the p-MA cohort (n = 54) vs. 8.1% (4.6%) in the r-MA cohort (n = 50) (p = .001). The percentage of subjects with body-weight loss >5% was 42.6% in the p-MA cohort vs. 68.0% in the r-MA cohort (p = .011). Tube feeding was needed in 22.2% of p-MA vs. 62.0% of r-MA patients (p < .001). Less neutropenia (26.0% vs. 70.0% [p < .001]) and a shorter duration of grade 3-4 mucositis (2.4 ± 1.4 vs. 3.6 ± 2.0 wk [p = .009]) were observed with p-MA treatment. Disease-specific survival, locoregional control, or distant metastasis-free survival did not differ. Less competing mortality from secondary primary cancer resulted in a better overall survival trend in the p-MA cohort.p-MA may reduce body-weight loss and improve adverse event profiles during CCRT for patients with PLSCC.

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.

Long-term use and risk of major adverse cardiac events: Comparing enzalutamide and abiraterone in chemotherapy-naïve patients with metastatic castration-resistant prostate cancer.

This is a retrospective cohort study by analyzing a multi-institutional electronic medical records database in Taiwan to compare long-term effectiveness and risk of major adverse cardiac events (MACE) in chemotherapy-naïve metastatic castration-resistant prostate cancer (mCRPC) patients treated with enzalutamide (ENZ) or abiraterone (AA). Patients aged 20 years and older and newly receiving androgen receptor targeted therapies ENZ or AA from September 2016 to December 2019 were included. We followed patients from initiation of therapies to the occurrence of outcomes (prostate-specific antigen (PSA) response rate, PSA progression free survival (PFS), overall survival (OS), and MACE), death, the last clinical visit, or December 31, 2020. We performed multivariable Cox proportional hazard models to compare ENZ and AA groups for the measured outcomes. A total of 363 patients treated with either ENZ (n = 157) or AA (n = 206) were identified. The analysis found a significantly higher proportion of patients with a PSA response rate higher than 50% among those receiving ENZ than among those receiving AA (ENZ vs AA: 75.80% vs 63.59%, P = .01). However, there was no significant difference in PSA PFS (adjusted hazard ratio: 0.86; 95% CI 0.63-1.17) and OS (0.68: 0.41-1.14) between the use of ENZ and AA in chemotherapy-naïve mCRPC patients. Regarding the cardiovascular (CV) safety outcome, there was a significantly lower risk of MACE in patients receiving ENZ, compared to patients receiving AA (0.20: 0.07-0.55). The findings suggest that enzalutamide may be more efficacious for PSA response and suitable for chemotherapy-naïve mCRPC patients with high CV risk profile.

Early relapse is an adverse prognostic factor for survival outcomes in patients with oral cavity squamous cell carcinoma: results from a nationwide registry study.

BACKGROUND: The prognostic significance of the relapse interval in patients with resected oral cavity squamous cell carcinoma (OCSCC) is a matter of ongoing debate. In this large-scale, registry-based, nationwide study, we examined whether the time interval between surgery and the first disease relapse may affect survival outcomes in Taiwanese patients with OCSCC. METHODS: Data made available by the Taiwan Health Promotion Administration as of 2004 were obtained. The study cohort consisted of patients who were included in the registry between 2011 and 2017. Disease staging was performed according to the American Joint Committee on Cancer (AJCC) Staging Manual, Eight Edition. We retrospectively reviewed the clinical records of 13,789 patients with OCSCC who received surgical treatment. A total of 2327 (16.9%) patients experienced a first disease relapse. The optimal cutoff value for the relapse interval was 330 days when both 5-year disease-specific survival (DSS) and overall survival (OS) (≤ 330/>330 days, n = 1630/697) were taken into account. In addition, we undertook a propensity score (PS)-matched analysis of patients (n = 654 each) with early (≤ 330 days) versus late (> 330 days) relapse. RESULTS: The median follow-up time in the entire study cohort was 702 days (433 and 2001 days in the early and late relapse groups, respectively). Compared with patients who experienced late relapse, those with early relapse showed a higher prevalence of the following adverse prognostic factors: pT4, pN3, pStage IV, poor differentiation, depth of invasion ≥ 10 mm, and extra-nodal extension. Multivariable analysis revealed that early relapse was an independent adverse prognostic factor for both 5-year DSS and OS (average hazard ratios [AHRs]: 3.24 and 3.91, respectively). In the PS-matched cohort, patients who experienced early relapse showed less favorable 5-year DSS: 58% versus 30%, p < 0.0001 (AHR: 3.10 [2.69 - 3.57]) and OS: 49% versus 22%, p < 0.0001 (AHR: 3.32 [2.89 - 3.81]). CONCLUSION: After adjustment for potential confounders and PS matching, early relapse was an adverse prognostic factor for survival outcomes in patients with OCSCC. Our findings may have significant implications for risk stratification.

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.

Associations of prognostic-awareness-transition patterns with end-of-life care in cancer patients' last month.

PURPOSE: Cancer patients heterogeneously develop prognostic awareness, and end-of-life cancer care has become increasingly aggressive to the detriment of patients and healthcare sustainability. We aimed to explore the never-before-examined associations of prognostic-awareness-transition patterns with end-of-life care. METHODS: Prognostic awareness was categorized into four states: (1) unknown and not wanting to know; (2) unknown but wanting to know; (3) inaccurate awareness; and (4) accurate awareness. We examined associations of our previously identified three prognostic-awareness-transition patterns during 334 cancer patients' last 6 months (maintaining accurate prognostic awareness, gaining accurate prognostic awareness, and maintaining inaccurate/unknown prognostic awareness) and end-of-life care (cardiopulmonary resuscitation, intensive care unit care, mechanical ventilation, chemotherapy/immunotherapy, and hospice care) in cancer patients' last month by multivariate logistic regressions. RESULTS: Cancer patients in the maintaining-accurate-prognostic-awareness and gaining-accurate-prognostic-awareness groups had significantly lower odds of cardiopulmonary resuscitation (adjusted odds ratio [95% confidence interval]: 0.22 [0.06-0.78]; and 0.10 [0.01-0.97], respectively) but higher odds of hospice care (3.44 [1.64-7.24]; and 3.28 [1.32-8.13], respectively) in the last month than those in the maintaining inaccurate/unknown prognostic awareness. The maintaining-accurate-prognostic-awareness group had marginally lower odds of chemotherapy or immunotherapy received than the gaining-accurate-prognostic-awareness group (0.58 [0.31-1.10], p = .096]). No differences in intensive care unit care and mechanical ventilation among cancer patients in different prognostic-awareness-transition patterns were observed. CONCLUSION: End-of-life care received in cancer patients' last month was associated with the three distinct prognostic-awareness-transition patterns. Cancer patients' accurate prognostic awareness should be facilitated earlier to reduce their risk of receiving aggressive end-of-life care, especially for avoiding chemotherapy/immunotherapy close to death. TRIAL REGISTRATION: ClinicalTrials.gov:NCT01912846.

Conjoint cognitive and emotional death-preparedness states and their changes within cancer patients' last 6 months.

BACKGROUND/OBJECTIVE: Cognitive prognostic awareness (PA) and emotional preparedness for death are distinct but related concepts that have rarely been investigated conjointly and without considering the dynamic nature of death preparedness. To fill this gap, this secondary-analysis study identified distinct patterns/states of death preparedness and their changes within cancer patients' last 6 months. METHODS: Distinct death-preparedness states, determined by conjoint cognitive PA and emotional preparedness for death, as well as their changes between consecutive times were identified and estimated, respectively, by latent transition modeling with hidden Markov modeling among 383 cancer patients within their last 6 months. RESULTS: Four death-preparedness states (prevalence) were initially identified: no death preparedness (17.1%), cognitive death preparedness only (23.3%), emotional death preparedness only (39.9%), and sufficient death preparedness (19.7%). Patients in the no-death-preparedness state had neither accurate PA nor adequate emotional preparedness for death. The sufficient-death-preparedness state was characterized by both accurate PA and adequate emotional preparedness for death. In the cognitive- and emotional-death-preparedness-only states, patients were accurately aware of their prognosis and adequately emotionally prepared for their forthcoming death only, respectively. As death approached, state prevalence fluctuated within a narrow range for the no- and sufficient-death-preparedness states, whereas prevalence of cognitive- and emotional-death-preparedness-only states increased and decreased substantially, respectively. CONCLUSION: Cancer patients heterogeneously experienced conjoint cognitive PA and emotional preparedness for death, and prevalence of death-preparedness states changed substantially as death approached. Effective interventions are warranted to cultivate cognitive PA and facilitate emotional death-preparedness to improve end-of-life-care quality, thereby helping patients achieve a good death.

Purely laparoscopic feeding jejunostomy: a procedure which deserves more attention.

BACKGROUND: Laparoscopic procedure has inherent merits of smaller incisions, better cosmesis, less postoperative pain, and earlier recovery. In the current study, we presented our method of purely laparoscopic feeding jejunostomy and compared its results with that of conventional open approach. METHODS: We retrospectively reviewed our patients from 2012 to 2019 who had received either laparoscopic jejunostomy (LJ, n = 29) or open ones (OJ, n = 94) in Chang Gung Memorial Hospital, Linkou. Peri-operative data and postoperative outcomes were analyzed. RESULTS: In the current study, we employed 3-0 Vicryl, instead of V-loc barbed sutures, for laparoscopic jejunostomy. The mean operative duration of LJ group was about 30 min longer than the OJ group (159 ± 57.2 mins vs 128 ± 34.6 mins; P = 0.001). There were no intraoperative complications reported in both groups. The patients in the LJ group suffered significantly less postoperative pain than in the OJ group (mean NRS 2.03 ± 0.9 vs. 2.79 ± 1.2; P = 0.002). The majority of patients in both groups received early enteral nutrition (< 48 h) after the operation (86.2% vs. 74.5%; P = 0.143). CONCLUSIONS: Our study demonstrated that purely laparoscopic feeding jejunostomy is a safe and feasible procedure with less postoperative pain and excellent postoperative outcome. It also provides surgeons opportunities to enhance intracorporeal suture techniques.

A combined analysis of maximum standardized uptake value on FDG-PET, genetic markers, and clinicopathological risk factors in the prognostic stratification of patients with resected oral cavity squamous cell carcinoma.

OBJECTIVE: Clinical outcomes of patients with resected oral cavity squamous cell carcinoma (OCSCC) chiefly depend on the presence of specific clinicopathological risk factors (RFs). Here, we performed a combined analysis of FDG-PET, genetic markers, and clinicopathological RFs in an effort to improve prognostic stratification. METHODS: We retrospectively reviewed the clinical records of 2036 consecutive patients with first primary OCSCC who underwent surgery between 1996 and 2016. Of them, 345 underwent ultra-deep targeted sequencing (UDTS, between 1996 and 2011) and 168 whole exome sequencing (WES, between 2007 and 2016). Preoperative FDG-PET imaging was performed in 1135 patients from 2001 to 2016. Complete data on FDG-PET, genetic markers, and clinicopathological RFs were available for 327 patients. RESULTS: Using log-ranked tests based on 5-year disease-free survival (DFS), the optimal cutoff points for maximum standardized uptake values (SUV-max) of the primary tumor and neck metastatic nodes were 22.8 and 9.7, respectively. The 5-year DFS rates were as follows: SUVtumor-max ≥ 22.8 or SUVnodal-max ≥ 9.7 (n = 77) versus SUVtumor-max < 22.8 and SUVnodal-max < 9.7 (n = 250), 32%/62%, P < 0.001; positive UDTS or WES gene panel (n = 64) versus negative (n = 263), 25%/62%, P < 0.001; pN3b (n = 165) versus pN1-2 (n = 162), 42%/68%, P < 0.001. On multivariate analyses, SUVtumor-max ≥ 22.8 or SUVnodal-max ≥ 9.7, a positive UDTS/WES gene panel, and pN3b disease were identified as independent prognosticators for 5-year outcomes. Based on these variables, we devised a scoring system that identified four distinct prognostic groups. The 5-year rates for patients with a score from 0 to 3 were as follows: loco-regional control, 80%/67%/47%/24% (P < 0.001); distant metastases, 13%/23%/55%/92% (P < 0.001); DFS, 74%/58%/28%/7% (P < 0.001); and disease-specific survival, 80%/64%/35%/7% (P < 0.001) respectively. CONCLUSIONS: The combined assessment of tumor and nodal SUV-max, genetic markers, and pathological node status may refine the prognostic stratification of OCSCC patients.

Prognostic and predictive factors for Taiwanese patients with advanced biliary tract cancer undergoing frontline chemotherapy with gemcitabine and cisplatin: a real-world experience.

BACKGROUND: Chemotherapy with gemcitabine and cisplatin has been the standard of care in first-line chemotherapy for advanced biliary tract cancer (BTC) since the trial ABC-02 was published in 2010. We aimed to investigate the prognostic and predictive factors of this regimen in a cohort of Taiwanese patients with advanced BTC. METHODS: A total of 118 patients with histologically confirmed BTC treated at Chang Gung Memorial Hospital at Linkou from 2012 to 2017 were retrospectively reviewed. RESULTS: The median progression-free survival (PFS) and overall survival (OS) were 3.6 months and 8.4 months, respectively. In the multivariate analysis, neutrophil to lymphocyte ratio (NLR) > 7.45, biliary drainage requiring both percutaneous transhepatic cholangiography drainage (PTCD) and internal stenting, and tumor responses with progressive diseases and not assessed were independent poor prognostic factors for PFS. Male sex, NLR > 7.45, alkaline phosphatase> 94 U/L, biliary drainage requiring both PTCD and internal stenting, and tumor responses with stable disease, progressive diseases and not assessed were independent poor prognostic factors for OS. Monocyte to lymphocyte ratio (MLR) ≤ 0.28 was the only significant predictive factor for the tumor response. Patients with complete response/partial response had significantly lower MLR than patients with other tumor responses. CONCLUSION: We identified three important prognostic factors, namely tumor response, NLR, and biliary drainage requiring both PTCD and internal stenting for both PFS and OS. MLR was the only significant predictive factor for the tumor response. These findings could provide physicians with more information to justify the clinical outcomes in patients with advanced BTC in real-world practice.

Evaluating if an Advance Care Planning Intervention Promotes Do-Not-Resuscitate Orders by Facilitating Accurate Prognostic Awareness.

BACKGROUND: Issuing do-not-resuscitate (DNR) orders has seldom been an outcome in randomized clinical trials of advance care planning (ACP) interventions. The aim of this study was to examine whether an ACP intervention facilitating accurate prognostic awareness (PA) for patients with advanced cancer was associated with earlier use of DNR orders. PATIENTS AND METHODS: Participants (n=460) were randomly assigned 1:1 to the experimental and control arms, with 392 deceased participants constituting the final sample of this secondary analysis study. Participants in the intervention and control arms had each received an intervention tailored to their readiness for ACP/prognostic information and symptom-management education, respectively. Effectiveness in promoting a DNR order by facilitating accurate PA was determined by intention-to-treat analysis using multivariate logistic regression with hierarchical linear modeling. RESULTS: At enrollment in the ACP intervention and before death, 9 (4.6%) and 8 (4.1%) participants and 168 (85.7%) and 164 (83.7%) participants in the experimental and control arms, respectively, had issued a DNR order, without significant between-arm differences. However, participants in the experimental arm with accurate PA were significantly more likely than participants in the control arm without accurate PA to have issued a DNR order before death (adjusted odds ratio, 2.264; 95% CI, 1.036-4.951; P=.041). Specifically, participants in the experimental arm who first reported accurate PA 31 to 90 days before death were significantly more likely than their counterparts in the control arm who reported accurate PA to have issued a DNR order in the next wave of assessment (adjusted odds ratio, 13.365; 95% CI, 1.989-89.786; P=.008). Both arms issued DNR orders close to death (median, 5-6 days before death). CONCLUSIONS: Our ACP intervention did not promote the overall presence of a DNR order. However, our intervention facilitated the issuance of NDR orders before death among patients with accurate PA, especially those who reported accurate PA 31 to 90 days before death, but it did not facilitate the issuance of DNR orders earlier than their counterparts in the control arm.ClinicalTrial.gov Identification: NCT01912846.

Novel circulating tumor cell-based blood test for the assessment of PD-L1 protein expression in treatment-naïve, newly diagnosed patients with non-small cell lung cancer.

We evaluated the analytical and clinical performance of a novel circulating tumor cell (CTC)-based blood test for determination of programmed death ligand 1 (PD-L1) protein expression status in real time in treatment-naïve non-small cell lung cancer (NSCLC) patients. CTCs were detected in 86% of patients with NSCLC (I-IV) at the time of diagnosis, with a 67% PD-L1 positivity rate (≥ 1 PDL + CTC). Among 33 NSCLC patients with PD-L1 results available via both tissue immunohistochemistry (IHC) and CTC assays, 78.9% were positive according to both methods. The CTC test identified an additional ten cases that were positive for PD-L1 expression but that tested negative via IHC analysis. Detection of higher PD-L1 expression on CTCs compared to that in the corresponding tissue was concordant with data obtained using other platforms in previously treated patients. The concordance in PD-L1 expression between tissue and CTCs was approximately 57%, which is higher than that reported by others. In summary, evaluation of PD-L1 protein expression status on CTCs isolated from NSCLC patients is feasible. PD-L1 expression status on CTCs can be determined serially during the disease course, thus overcoming the myriad challenges associated with tissue analysis.

Tumor Depth of Invasion (Tumor > 4 cm/Depth > 10 mm and Depth > 20 mm) and Through Cortex/Skin Invasion are Both Valid Criteria for Classifying Tumors as pT4a in AJCC 2018 Oral Cavity Cancer Staging System.

BACKGROUND: According to the AJCC third to seventh edition staging manuals (1988-2010), the presence of through cortex and/or skin invasion in oral cavity squamous cell carcinoma (OCSCC) identifies T4a tumors. The AJCC eighth edition (2018) introduced a depth of invasion (DOI) > 20 mm as a criterion for pT4a. Subsequently, a revision maintained that tumors > 4 cm with a DOI > 10 mm should be classified as pT4a. We sought to analyze the prognostic impact of the three distinct criteria identifying pT4a disease. METHODS: We examined 667 consecutive patients with pT3-4 buccal/gum/hard palate/retromolar SCC who underwent surgery between 1996 and 2016. pT1/pT2 (n = 108/359) disease were included for comparison purposes. RESULTS: The 5-year outcomes of patients with pT1/pT2/without (n = 406)/with tumor > 4 cm/DOI > 10 mm (n = 261), pT1/pT2/DOI ≤ 20 mm (n = 510)/> 20 mm (n = 157), and pT1/pT2/without (n = 305)/with through cortex/skin invasion (n = 362) were as follows: disease-specific survival (DSS), 98%/89%/79%/65%, p < 0.001, 98%/89%/78%/59%, p < 0.001, and 98%/89%79%/69%, p < 0.001; overall survival (OS), 90%/79%/63%/51%, p < 0.001, 90%/79%/63%/42%, p < 0.001, and 90%/79%/65%/52%, p < 0.001. In pT3-4 disease, a tumor > 4 cm/DOI > 10 mm was an independent adverse prognosticator for 5-year DSS rate, DOI > 20 mm was an independent adverse prognosticator for 5-year DSS and OS rates, whereas through cortex/skin invasion independently predicted 5-year OS rates. CONCLUSIONS: All of the three criteria (tumor > 4 cm/DOI > 10 mm, DOI > 20 mm, and through cortex/skin invasion) identify high-risk patients, which should be reflected in further revisions of pT4a classification in OCSCC.

Advance Care Planning Improves Psychological Symptoms But Not Quality of Life and Preferred End-of-Life Care of Patients With Cancer.

BACKGROUND: This study was conducted to examine whether a longitudinal advance care planning (ACP) intervention facilitates concordance between the preferred and received life-sustaining treatments (LSTs) of terminally ill patients with cancer and improves quality of life (QoL), anxiety symptoms, and depressive symptoms during the dying process. PATIENTS AND METHODS: Of 795 terminally ill patients with cancer from a medical center in Taiwan, 460 were recruited and randomly assigned 1:1 to the experimental and control arms. The experimental arm received an interactive ACP intervention tailored to participants' readiness to engage in this process. The control arm received symptom management education. Group allocation was concealed, data collectors were blinded, and treatment fidelity was monitored. Outcome measures included 6 preferred and received LSTs, QoL, anxiety symptoms, and depressive symptoms. Intervention effectiveness was evaluated by intention-to-treat analysis. RESULTS: Participants providing data had died through December 2017. The 2 study arms did not differ significantly in concordance between the 6 preferred and received LSTs examined (odds ratios, 0.966 [95% CI, 0.653-1.428] and 1.107 [95% CI, 0.690-1.775]). Participants who received the ACP intervention had significantly fewer anxiety symptoms (ß, -0.583; 95% CI, -0.977 to -0.189; P= .004) and depressive symptoms (ß, -0.533; 95% CI, -1.036 to -0.030; P= .038) compared with those in the control arm, but QoL did not differ. CONCLUSIONS: Our ACP intervention facilitated participants' psychological adjustment to the end-of-life (EoL) care decision-making process, but neither improved QoL nor facilitated EoL care honoring their wishes. The inability of our intervention to improve concordance may have been due to the family power to override patients' wishes in deeply Confucian doctrine-influenced societies such as Taiwan. Nevertheless, our findings reassure healthcare professionals that such an ACP intervention does not harm but improves the psychological well-being of terminally ill patients with cancer, thereby encouraging physicians to discuss EoL care preferences with patients and involve family caregivers in EoL care decision-making to eventually lead to patient value-concordant EoL cancer care.

Associations of preloss and postloss factors with severe depressive symptoms and quality of life over the first 2 years of bereavement for family caregivers of terminally ill cancer patients.

BACKGROUND: Family caregivers carry heavy end-of-life (EOL) caregiving burdens, with their physical and psychological well-being threatened from caregiving to bereavement. However, caregiving burden has rarely been examined as a risk factor for bereavement adjustment to disentangle the wear-and-tear vs relief models of bereavement. Objective/Methods Preloss and postloss variables associated with severe depressive symptoms and quality of life (QOL) for 201 terminally ill cancer patients' caregivers over their first 2 years of bereavement were simultaneously evaluated using multivariate hierarchical linear modeling. Severe depressive symptoms (Center for Epidemiological Studies Depression Scale score > 16) and QOL (physical and mental component summaries of the Medical Outcomes Study Short-Form Health Survey) were measured 1, 3, 6, 13, 18, and 24 months postloss. RESULTS: Caregivers' likelihood of severe depressive symptoms and mental health-related QOL improved significantly from the second year and throughout the first 2 years of bereavement, respectively, whereas physical health-related QOL remained steady over time. Higher subjective caregiving burden and postloss concurrent greater social support and better QOL were associated with bereaved caregivers' lower likelihood of severe depressive symptoms. Bereaved caregivers' mental health-related QOL was facilitated and impeded by concurrent greater perceived social support and severe depressive symptoms, respectively. CONCLUSION: Severe depressive symptoms and mental health-related QOL improved substantially, whereas physical health-related QOL remained steady over the first 2 years of bereavement for cancer patients' caregivers. Timely referrals to adequate bereavement services should be promoted for at-risk bereaved caregivers, thus addressing their support needs and facilitating their bereavement adjustment.

Accurate prognostic awareness and preference states influence the concordance between terminally ill cancer patients' states of preferred and received life-sustaining treatments in the last 6 months of life.

BACKGROUND: Factors facilitating/hindering concordance between preferred and received life-sustaining treatments may be distorted if preferences and predictors are measured long before death. AIM: To examine factors facilitating/hindering concordance between cancer patients' preferred and received life-sustaining-treatment states in their last 6 months. DESIGN: Longitudinal, observational design. SETTING/PARTICIPANTS: States of preferred and received life-sustaining treatments (cardio-pulmonary resuscitation, intensive care unit care, cardiac massage, intubation with mechanical ventilation, intravenous nutritional support, and nasogastric tube feeding) were examined in 218 Taiwanese cancer patients by a latent transition model with hidden Markov modeling. Multivariate logistic regression modeling was used to examine factors facilitating/hindering concordance between preferred and received life-sustaining-treatment states. RESULTS: Concordance between preferred and received life-sustaining-treatment states was poor (40.8%, kappa value (95% confidence interval): 0.05 [-0.03, 0.14]). Patients who accurately understood their prognosis and preferred comfort care were significantly more likely to receive preferred life-sustaining treatments before death than those who did not know their prognosis but wanted to know, those who were uniformly uncertain about what life-sustaining treatments they preferred to receive, and those who preferred nutritional support but declined other life-sustaining treatments. Patient age, physician-patient end-of-life-care discussions, symptom distress, and functional dependence were not associated with concordance between preferred and received life-sustaining-treatment states. CONCLUSION: Prognostic awareness and preferred states of life-sustaining treatments were significantly associated with concordance between preferred and received life-sustaining-treatment states. Personalized interventions should be developed to cultivate terminally ill cancer patients' accurate prognostic awareness, allowing them to formulate realistic life-sustaining-treatment preferences and facilitating their receiving value-concordant end-of-life care.

Mechanical property characterization of hundreds of single nuclei based on microfluidic constriction channel.

As label-free biomarkers, the mechanical properties of nuclei are widely treated as promising biomechanical markers for cell type classification and cellular status evaluation. However, previously reported mechanical parameters were derived from only around 10 nuclei, lacking statistical significances due to low sample numbers. To address this issue, nuclei were first isolated from SW620 and A549 cells, respectively, using a chemical treatment method. This was followed by aspirating them through two types of microfluidic constriction channels for mechanical property characterization. In this study, hundreds of nuclei were characterized, producing passage times of 0.5 ± 1.2 s for SW620 nuclei in type I constriction channel (n = 153), 0.045 ± 0.047 s for SW620 nuclei in type II constriction channel (n = 215) and 0.50 ± 0.86 s for A549 nuclei in type II constriction channel. In addition, neural network based pattern recognition was used to classify the nuclei isolated from SW620 and A549 cells, producing successful classification rates of 87.2% for diameters of nuclei, 85.5% for passage times of nuclei and 89.3% for both passage times and diameters of nuclei. These results indicate that the characterization of the mechanical properties of nuclei may contribute to the classification of different tumor cells.