Clinical practice consensus for the diagnosis and management of melanoma in Taiwan.

Melanoma is rare in Taiwan. Asian melanoma is distinct from Western melanoma because acral and mucosal melanoma accounts for the majority of melanoma cases, leading to distinct tumor behaviors and genetic profiling. With consideration of the clinical guidelines in Western countries, Taiwanese experts developed a local clinical practice consensus guideline. This consensus includes diagnosis, staging, and surgical and systemic treatment, based only on clinical evidence, local epidemiology, and available resources evaluated by experts in Taiwan. This consensus emphasizes the importance of surgical management, particularly for sentinel lymph node biopsies. In addition, molecular testing for BRAF is mandatory for patients before systemic treatment. Furthermore, immunotherapy and targeted therapy are prioritized for systemic treatment. This consensus aimed to assist clinicians in Taiwan in diagnosing and treating patients according to available evidence.

Focused ultrasound combined with radiotherapy for malignant brain tumor: a preclinical and clinical study.

INTRODUCTION: Blood-brain barrier (BBB) remains to be the major obstacle to conquer in treating patients with malignant brain tumors. Radiation therapy (RT), despite being the mainstay adjuvant modality regardless of BBB, the effect of radiation induced cell death is hindered by the hypoxic microenvironment. Focused ultrasound (FUS) combined with systemic microbubbles has been shown not only to open BBB but also potentially increased regional perfusion. However, no clinical study has investigated the combination of RT with FUS-BBB opening (RT-FUS). METHODS: We aimed to provide preclinical evidence of RT-FUS combination in GBM animal model, and to report an interim analysis of an ongoing single arm, prospective, pilot study (NCT01628406) of combining RT-FUS for recurrent malignant high grade glioma patients, of whom re-RT was considered for disease control. In both preclinical and clinical studies, FUS-BBB opening was conducted within 2 h before RT. Treatment responses were evaluated by objective response rate (ORR) using magnetic resonance imaging, progression free survival, and overall survival, and adverse events (AE) in clinical study. Survival analysis was performed in preclinical study and descriptive analysis was performed in clinical study. RESULTS: In mouse GBM model, the survival analysis showed RT-FUS (2 Gy) group was significantly longer than RT (2 Gy) group and control, but not RT (5 Gy) group. In the pilot clinical trial, an interim analysis of six recurrent malignant high grade glioma patients underwent a total of 24 RT-FUS treatments was presented. Three patients had rapid disease progression at a mean of 33 days after RT-FUS, while another three patients had at least stable disease (mean 323 days) after RT-FUS with or without salvage chemotherapy or target therapy. One patient had partial response after RT-FUS, making the ORR of 16.7%. There was no FUS-related AEs, but one (16.7%) re-RT-related grade three radiation necrosis. CONCLUSION: Reirradiation is becoming an option after disease recurrence for both primary and secondary malignant brain tumors since systemic therapy significantly prolongs survival in cancer patients. The mechanism behind the synergistic effect of RT-FUS in preclinical model needs further study. The clinical evidence from the interim analysis of an ongoing clinical trial (NCT01628406) showed a combination of RT-FUS was safe (no FUS-related adverse effect). A comprehensive analysis of radiation dosimetry and FUS energy distribution is expected after completing the final recruitment.

MAP3K1 expression is associated with progression and poor prognosis of hormone receptor-positive, HER2-negative early-stage breast cancer.

PURPOSE: In this study, we assessed whether the overexpression of MAP3K1 promotes the proliferation, migration, and invasion of breast cancer cells, which affect the prognosis of hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative early stage breast cancer. METHODS: Two HR-positive, HER2-negative breast cancer cell lines (MCF7 and T-47D) overexpressing MAP3K1 were transfected with two MAP3K1 short hairpin RNA plasmids (shMAP3K1 [#3] and shMAP3K1 [#5]). The proliferation, migration, and invasion of these cells were then examined. We assessed whether shMAP3K1 affects the cell cycle, levels of downstream signaling molecules (ERK, JNK, p38 MAPK, and NF-κB), and sensitivity to chemotherapeutic and hormonal agents. To assess the anti-tumor effect of MAP3K1 knockdown in the breast cancer orthotopic model, MCF7 and T-47D cells treated with or without shMAP3K1 (#3) and shMAP3K1 (#5) were inoculated into the mammary fat pads of mice. In total, 182 patients with HR-positive, HER2-negative T1 and T2 breast cancer and 0-3 nodal metastases were included. Additionally, 73 patients with T1 and T2 breast cancer and negative nodes who received adjuvant endocrine therapy alone were selected as an independent validation cohort. RESULTS: In both cell lines, shMAP3K1 (#3) and shMAP3K1 (#5) significantly reduced cell growth, migration, and invasion by downregulating MMP-9 and by blocking the G2/M phase of the cell cycle and its regulatory molecule cyclin B1. Moreover, both shMAP3K1 (#3) and shMAP3K1 (#5) downregulated ERK-, JNK-, p38 MAPK-, and NF-κB-dependent gene transcription and enhanced the sensitivity of both cell lines to doxorubicin, docetaxel, and tamoxifen. We observed that both shMAP3K1 (#3) and shMAP3K1 (#5) inhibited tumor growth compared with that in the scrambled group of MCF7 and T-47D cell orthotopic tumors. Patients with MAP3K1 overexpression exhibited significantly poorer 10-year disease-free survival (DFS) (70.4% vs. 88.6%, p = 0.003) and overall survival (OS) (81.9% vs. 96.3%, p = 0.001) than those without MAP3K1 overexpression. Furthermore, phospho-ERK (p < 0.001) and phospho-JNK (p < 0.001) expressions were significantly associated with MAP3K1 expression, and both phospho-ERK and phospho-JNK expressions were significantly correlated with poor 10-year DFS and OS. These biological findings, including a significant association between DFS and OS, and the expressions of MAP3K1, phospho-ERK, and phospho-JNK were further validated in an independent cohort. Multivariate analysis identified MAP3K1 expression as an independent poor prognostic factor for DFS and OS. CONCLUSION: Our results indicate that the overexpression of MAP3K1 plays a major role in the poor prognosis of HR-positive, HER2-negative early stage breast cancer.

Immune Checkpoint Inhibitor, Nivolumab, Combined with Chemotherapy Improved the Survival of Unresectable Advanced and Metastatic Esophageal Squamous Cell Carcinoma: A Real-World Experience.

Patients with advanced esophageal squamous cell carcinoma (SCC) have a poor prognosis when treated with standard chemotherapy. Programmed death ligand 1 (PD-L1) expression in esophageal cancer has been associated with poor survival and more advanced stage. Immune checkpoint inhibitors, such as PD-1 inhibitors, showed benefits in advanced esophageal cancer in clinical trials. We analyzed the prognosis of patients with unresectable esophageal SCC who received nivolumab with chemotherapy, dual immunotherapy (nivolumab and ipilimumab), or chemotherapy with or without radiotherapy. Patients who received nivolumab with chemotherapy had a better overall response rate (ORR) (72% vs. 66.67%, p = 0.038) and longer overall survival (OS) (median OS: 609 days vs. 392 days, p = 0.04) than those who received chemotherapy with or without radiotherapy. In patients receiving nivolumab with chemotherapy, the duration of the treatment response was similar regardless of the treatment line they received. According to clinical parameters, liver and distant lymph nodes metastasis showed a trend of negative and positive impacts, respectively, on treatment response in the whole cohort and in the immunotherapy-containing regimen cohort. Nivolumab add-on treatment showed less gastrointestinal and hematological adverse effects, compare with chemotherapy. Here, we showed that nivolumab combined with chemotherapy is a better choice for patients with unresectable esophageal SCC.

Achieving Net Zero-An Illustration of Carbon Emissions Reduction with A New Meta-Inverse DEA Approach.

To achieve the goal of limiting global warming to 1.5 °C above preindustrial levels, net-zero emissions targets were proposed to assist countries in planning their long-term reduction. Inverse Data Envelopment Analysis (DEA) can be used to determine optimal input and output levels without sacrificing the set environmental efficiency target. However, treating countries as having the same capability to mitigate carbon emissions without considering their different developmental stages is not only unrealistic but also inappropriate. Therefore, this study incorporates a meta-concept into inverse DEA. This study adopts a three-stage approach. In the first stage, a meta-frontier DEA method is adopted to assess and compare the eco-efficiency of developed and developing countries. In the second stage, the specific super-efficiency method is adopted to rank the efficient countries specifically focused on carbon performance. In the third stage, carbon dioxide emissions reduction targets are proposed for the developed and developing countries separately. Then, a new meta-inverse DEA method is used to allocate the emissions reduction target to the inefficient countries in each of the specific groups. In this way, we can find the optimal CO2 reduction amount for the inefficient countries with unchanged eco-efficiency levels. The implications of the new meta-inverse DEA method proposed in this study are twofold. The method can identify how a DMU can reduce undesirable outputs without sacrificing the set eco-efficiency target, which is especially useful in achieving net-zero emissions since this method provides a roadmap for decision-makers to understand how to allocate the emissions reduction targets to different units. In addition, this method can be applied to heterogeneous groups where they are assigned to different emissions reduction targets.

Delay of Surgery for Spinal Metastasis due to the COVID-19 Outbreak Affected Patient Outcomes.

OBJECTIVE: The present study is to analyze the effects of the coronavirus disease 2019 (COVID 2019) outbreak and the subsequent lockdown on the outcomes of spinal metastasis patients. METHODS: The study was a retrospective analysis of data from a prospective cohort study. All patients underwent surgical intervention for spinal metastases between January 2019 and December 2021 and had at least 3 months of postoperative follow-up. The primary outcome was overall mortality during the 4 different stages (pre-COVID-19 era, COVID-19 pandemic except in Taiwan, national lockdown, lifting of the lockdown). The secondary outcomes were the oncological severity scores, medical/surgical accessibility, and patient functional outcome during the 4 periods as well as survival/mortality. RESULTS: A total of 233 patients were included. The overall mortality rate was 41.20%. During the Taiwan lockdown, more patients received palliative surgery than other surgical methods, and no total en bloc spondylectomy was performed. The time from surgeon visit to operation was approximately doubled after the COVID-19 outbreak in Taiwan (75.97, 86.63, 168.79, and 166.91 hours in the 4 periods, respectively). The estimated survival probability was highest after the national lockdown was lifted and lowest during the lockdown. In the multivariate analysis, increased risk of mortality was observed with delay of surgery, with emergency surgery having a higher risk with delays above 33 hours, urgent surgery (below 59 and above 111 hours), and elective surgery (above 332 hours). CONCLUSION: The COVID-19 pandemic and related policies have altered daily clinical practice and negatively impacted the survival of patients with spinal metastases.

The Yale Food Addiction Scale 2.0 and the modified Yale Food Addiction Scale 2.0 in Taiwan: Factor structure and concurrent validity.

Introduction: The most widely used instruments to assess food addiction - the Yale Food Addiction Scale 2.0 (YFAS 2.0) and its modified version (mYFAS 2.0) - have not been validated in a Taiwanese population. The present study compared the psychometric properties between the Taiwan versions of YFAS 2.0 and mYFAS 2.0 among university students. Methods: An online survey comprising the YFAS 2.0, mYFAS 2.0, Weight Self-Stigma Questionnaire (WSSQ) and International Physical Activity Questionnaire-Short Form (IPAQ-SF) were used to assess food addiction, self-stigma, and physical activity. Results: All participants (n = 687; mean age = 24.00 years [SD ± 4.48 years]; 407 females [59.2%]) completed the entire survey at baseline and then completed the YFAS 2.0 and mYFAS 2.0 again three months later. The results of confirmatory factor analysis (CFA) indicated that the YFAS 2.0 and mYFAS 2.0 both shared a similar single-factor solution. In addition, both the YFAS 2.0 and mYFAS 2.0 reported good internal consistency (Cronbach's α = 0.90 and 0.89), good test-retest reliability (ICC = 0.71 and 0.69), and good concurrent validity with the total scores being strongly associated with the WSSQ (r = 0.54 and 0.57; p < 0.01), and less strongly associated with BMI (r = 0.17 and 0.13; p < 0.01) and IPAQ-SF (r = 0.23 and 0.25; p < 0.01). Discussion: Based on the findings, the Taiwan versions of the YFAS 2.0 and mYFAS 2.0 appear to be valid and reliable instruments assessing food addiction.

Yale Food Addiction Scale 2.0 (YFAS 2.0) and modified YFAS 2.0 (mYFAS 2.0): Rasch analysis and differential item functioning.

BACKGROUND: Food addiction (FA) is a prevalent concern that may manifest as poorly controlled food consumption and promote overweight/obesity. Thus, having a well-established instrument for assessment may facilitate better prevention and treatment. The current study investigated the psychometric properties of two common measures of FA (i.e., the Yale Food Addiction Scale [YFAS] 2.0 and its modified version, mYFAS 2.0) using a robust statistical analysis (Rasch model). METHODS: In this cross-sectional study, the scales were sent to 974 students studying in higher education (60% females) in Taiwan through online media including email and social networks. Rasch modeling was used to assess dimensionality, difficulty level, and item misfit and hierarchy. Differential item functioning (DIF) was performed to examine consistency of the items across gender and weight status. RESULTS: Rasch analysis indicated 3 items of the 35 items belonging to the YFAS 2.0 (8.6%) and none belonging to the mYFAS 2.0 were misfit. Unidimensionality and construct validity of both scales were supported by appropriate goodness-of-fit for diagnostic criteria. The person separation was 3.14 (reliability = 0.91) for the YFAS 2.0 and 2.17 (reliability = 0.82) for mYFAS 2.0, indicating the scales could distinguish participants into more than 3 strata. Only one substantial DIF was found for diagnostic criteria of "Failure to fulfill major role obligation" in the YFAS 2.0 across gender. CONCLUSION: According to Rasch modeling, both the YFAS 2.0 and mYFAS 2.0 have acceptable construct validity in Chinese-speaking youth. Scoring methods using either diagnostic criteria or symptom counts for both the YFAS 2.0 and mYFAS 2.0 are supported by the present Rasch findings.

Food addiction is related to eating disorders and may overlap with a variety of disorders, including binge-eating disorder, night-eating syndrome, bulimia nervosa or other conditions. Therefore, it is important for healthcare providers to assess food addiction and one commonly used method is using the Yale Food Addiction Scale (YFAS) developed by Gearhardt and her colleagues. The YFAS has been updated and revised into two versions: the YFAS 2.0 and modified YFAS 2.0 (i.e., mYFAS 2.0). Psychometric testing studies have reported the feasibility and adequate properties for both the YFAS 2.0 and mYFAS 2.0. However, prior studies' findings were based on classical test theory (CTT) findings. The present study thus used a modern test theory (i.e., Rasch models) to examine if both the YFAS 2.0 and mYFAS 2.0 have similarly satisfactory psychometric properties shown in the CTT findings. The present findings using Rasch models support the use of both the YFAS 2.0 and mYFAS 2.0 to assess food addiction among youth. Therefore, healthcare providers may use either the YFAS 2.0 or mYFAS 2.0 to assess levels of food addiction.

The perceived effects of augmented trail sensing and mood recognition abilities in a human-fish biohybrid system.

The use of technologies to enhance human and animal perception has been explored in pioneering research about artificial life and biohybrid systems. These attempts have revealed that augmented sensing abilities can emerge from new interactions between individuals within or across species. Nevertheless, the diverse effects of different augmented capabilities have been less examined and compared. In this work, we built a human-fish biohybrid system that enhanced the vision of the ornamental fish by projecting human participants onto the arena background. In contrast, human participants were equipped with a mixed-reality device, which visualized individual fish trails (representing situation-oriented perceptions) and emotions (representing communication-oriented perceptions). We investigated the impacts of the two enhanced perceptions on the human side and documented the perceived effects from three aspects. First, both augmented perceptions considerably increase participants' attention toward ornamental fish, and the impact of emotion recognition is more potent than trail sense. Secondly, the frequency of human-fish interactions increases with the equipped perceptions. The mood recognition ability on the human side can indirectly promote the recorded positive mood of fish. Thirdly, most participants mentioned that they felt closer to those fish which had mood recognition ability, even if we added some mistakes in the accuracy of mood recognition. In contrast, the addition of trail sensing ability does not lead to a similar effect on the mental bond. These findings reveal several aspects of different perceived effects between the enhancements of communication-oriented and situation-oriented perceptions.

COVID-19-Related Self-Stigma, Post-Traumatic Stress Disorder, Insomnia, and Smartphone Addiction Among Frontline Government Workers with COVID-19 Pandemic Control Duties.

Purpose: The duties related to COVID-19 control and prevention may have caused psychological stress for the individuals in charge (eg, frontline government workers) and have reportedly led to mental health issues, such as insomnia and post-traumatic stress disorder (PTSD). However, the prevalence of these COVID-19-related disorders and their associated factors remain unclear. Therefore, the purpose of the present study was to investigate the prevalence rates of insomnia, PTSD, COVID-19-related self-stigma, and smartphone addiction, along with the identification of risk factors and protective factors for Taiwan frontline government workers with COVID-19 pandemic control duties. Methods: The survey was carried out with 151 participants between September and October 2021. All participants completed the Fear of COVID-19 Scale (assessing fear of COVID-19), Self-Stigma Scale (assessing self-stigma during the COVID-19 pandemic), Smartphone Application-Based Addiction Scale (assessing the risk of smartphone addiction), Insomnia Severity Index (assessing insomnia), Impacts of Event Scale-6 (assessing PTSD), and a self-designed set of questions assessing trait resilience. Results: The results showed that the prevalence rate was 31.1% for insomnia and 33.8% for PTSD. Furthermore, service duration (adjusted odds ratio [AOR] = 0.93; 95% confidence interval [CI] = 0.86, 0.999) and trait resilience (AOR = 0.19; 95% CI = 0.08, 0.46) were protective factors and fear of COVID-19 (AOR = 1.91; 95% CI = 1.02, 3.57) was a risk factor for insomnia. Fear of COVID-19 (AOR = 2.63; 95% CI = 1.35, 5.14), self-stigma (AOR = 3.62; 95% CI = 1.19, 11.02), and smartphone addiction (AOR = 1.09, 95% CI = 1.001, 1.19) were risk factors, and trait resilience was a protective factor (AOR = 0.58; 95% CI = 0.29, 1.17) for PTSD. Conclusion: The findings demonstrated a high prevalence of insomnia and PTSD. Risk-reducing strategies and protective factor promotion strategies are recommended to help reduce the symptoms of insomnia and PTSD among Taiwan frontline government workers.

Matrin3 (MATR3) Expression Is Associated with Hemophagocytosis.

Hemophagocytic lymphohistiocytosis (HLH) is a life-threatening hyperinflammatory syndrome characterized by prolonged fever, cytopenia, hepatosplenomegaly, and hemophagocytosis. This occurs as a result of activated macrophages and impaired function of natural killer cells and/or cytotoxic T lymphocytes. The NF-κB pathway plays a crucial role in hyperinflammation. Matrin3 (MATR3) is a nuclear RNA/DNA-binding protein that plays multiple roles in the regulation of gene expression. We enroll 62 patients diagnosed with secondary HLH and hemophagocytosis. Peripheral blood (PB) from 25 patients and 30 healthy volunteers and good quality bone marrow (BM) samples from 47 patients are collected and used for analysis. Clinical parameters, including age, sex, etiology, ferritin, fibrinogen, triglyceride, and viral infection status, had no association with survival prediction. Patients with downregulation of NF-κB and MATR3mRNA expression in the BM had a higher mortality rate. MATR3mRNA expression in PB was lower in patients compared to that in healthy volunteers. We use shRNA-MATR3-KD-THP1 cells to determine the efficacy of phagocytosis. We note that shRNA-MATR3-KD-THP1 cells had a higher phagocytic effect on necrotic Jurkat E6 cells and carboxylate modified polystyrene latex beads. Herein, we provide evidence of a new marker for clinical translation that can serve as a potential treatment target for secondary HLH.

Rasch Modeling and Differential Item Functioning of the Self-Stigma Scale-Short Version among People with Three Different Psychiatric Disorders.

Self-stigma is prevalent in individuals with psychiatric disorders and can profoundly affect people. A unified assessment with sound psychometric properties is needed for evaluating self-stigma across psychiatric conditions. The aim of this study was to examine the psychometric properties of the Self-Stigma Scale-Short version (SSS-S) using Rasch modeling. Six-hundred and twelve participants with substance use disorders (n = 319), attention-deficit/hyperactivity disorder (n = 100), and schizophrenia (n = 193) completed the SSS-S. Rasch results confirmed the unidimensionality of the nine items of the SSS-S. The four-point Likert scale of the SSS-S reflected monotonical increases along the self-stigma continuum. No ceiling or floor effects were detected. Among the three subdomains of the SSS-S, cognitive items appeared to be the most robustly endorsed, and behavioral items were the least endorsed. Two items in the SSS-S displayed differential item functioning across the three diagnoses. Additionally, SSS-S scores showed weak to moderate correlation with depression, anxiety, and stress scale scores. The SSS-S had overall satisfactory psychometric properties. Healthcare professionals may use this assessment to assess self-stigma in multiple psychiatric groups, and information gained may facilitate improved care.

Investigation of the incidence trend of follicular lymphoma from 2008 to 2017 in Taiwan and the United States using population-based data.

BACKGROUND: The incidence of follicular lymphoma (FL) in Taiwan has not been well investigated since its inclusion as a histological subtype in the Taiwan Cancer Registry in 2008. The purpose of this study was to describe the incidence patterns of FL in Taiwan and compare the trends with those in other racial groups in the United States. MATERIALS AND METHODS: We conducted an epidemiological study using population-based data from the Taiwan Cancer Registry, Ministry of Health and Welfare, and the 18 Surveillance, Epidemiology, and End Results (SEER) registries to evaluate the FL incidence from 2008 to 2017. We calculated the annual percent change (APC) to describe the trends in the incidence of FL in subpopulations defined by race and sex over time. RESULTS: The annual age-adjusted incidence rate of FL in Taiwan increased significantly from 0.59 per 100,000 persons in 2008 to 0.82 per 100,000 persons in 2017, with an APC of 3.2. By contrast, the incidence rate in whites in the United States during the same period decreased from 3.42 to 2.74 per 100,000 persons, with an APC of -2.1. We found no significant change for the blacks (APC, -1.5%), Hispanics (APC, -0.7%), and Asians or Pacific Islanders (APC, +0.7%). The temporal trend was similar between the males and females. The relative frequency of FL among the incident non-Hodgkin lymphoma (NHL) cases also increased significantly in Taiwan from 7.64% in 2008 to 11.11% in 2017 (APC = 3.8). The relative frequency of FL among the incident NHL cases in the whites decreased from 2008 to 2012 (APC, -3.8%) and then stabilized after 2012 (APC, -0.2%). By contrast, little change in relative frequency of FL among the incident NHL cases was observed in the blacks, Hispanics, and APIs between 2008 and 2017. CONCLUSION: We found increases in the incidence of FL and the relative frequency of FL among the incident NHL cases in both males and females in Taiwan from 2008 to 2017. The FL incidence rates were unchanged for all races and sex groups in the United States, except for the decreases in the whites.

Nivolumab Combination Therapy in Advanced Esophageal Squamous-Cell Carcinoma.

BACKGROUND: First-line chemotherapy for advanced esophageal squamous-cell carcinoma results in poor outcomes. The monoclonal antibody nivolumab has shown an overall survival benefit over chemotherapy in previously treated patients with advanced esophageal squamous-cell carcinoma. METHODS: In this open-label, phase 3 trial, we randomly assigned adults with previously untreated, unresectable advanced, recurrent, or metastatic esophageal squamous-cell carcinoma in a 1:1:1 ratio to receive nivolumab plus chemotherapy, nivolumab plus the monoclonal antibody ipilimumab, or chemotherapy. The primary end points were overall survival and progression-free survival, as determined by blinded independent central review. Hierarchical testing was performed first in patients with tumor-cell programmed death ligand 1 (PD-L1) expression of 1% or greater and then in the overall population (all randomly assigned patients). RESULTS: A total of 970 patients underwent randomization. At a 13-month minimum follow-up, overall survival was significantly longer with nivolumab plus chemotherapy than with chemotherapy alone, both among patients with tumor-cell PD-L1 expression of 1% or greater (median, 15.4 vs. 9.1 months; hazard ratio, 0.54; 99.5% confidence interval [CI], 0.37 to 0.80; P<0.001) and in the overall population (median, 13.2 vs. 10.7 months; hazard ratio, 0.74; 99.1% CI, 0.58 to 0.96; P = 0.002). Overall survival was also significantly longer with nivolumab plus ipilimumab than with chemotherapy among patients with tumor-cell PD-L1 expression of 1% or greater (median, 13.7 vs. 9.1 months; hazard ratio, 0.64; 98.6% CI, 0.46 to 0.90; P = 0.001) and in the overall population (median, 12.7 vs. 10.7 months; hazard ratio, 0.78; 98.2% CI, 0.62 to 0.98; P = 0.01). Among patients with tumor-cell PD-L1 expression of 1% or greater, a significant progression-free survival benefit was also seen with nivolumab plus chemotherapy over chemotherapy alone (hazard ratio for disease progression or death, 0.65; 98.5% CI, 0.46 to 0.92; P = 0.002) but not with nivolumab plus ipilimumab as compared with chemotherapy. The incidence of treatment-related adverse events of grade 3 or 4 was 47% with nivolumab plus chemotherapy, 32% with nivolumab plus ipilimumab, and 36% with chemotherapy alone. CONCLUSIONS: Both first-line treatment with nivolumab plus chemotherapy and first-line treatment with nivolumab plus ipilimumab resulted in significantly longer overall survival than chemotherapy alone in patients with advanced esophageal squamous-cell carcinoma, with no new safety signals identified. (Funded by Bristol Myers Squibb and Ono Pharmaceutical; CheckMate 648 ClinicalTrials.gov number, NCT03143153.).

Risk of Subsequent Migraines in Facial Fracture Patients: A Population-Based Cohort Study.

Background: Limited studies have discussed the association between facial fractures and subsequent migraines. In this study, we examined this association and the effect of facial fracture and surgery on the development of migraines. Methods: We selected 5034 patients with facial fractures and a matched cohort of 20,136 patients without facial fractures or facial-associated surgery with a history of migraine from the National Health Insurance database. Risk factors included age, gender, occupation (white-collar, blue-collar, and others), and comorbidities. Patients were frequency matched by age, gender, and index year. The incidence of migraine and the association between migraine development and facial surgery were identified by facial fracture location stratification. Results: The incidence of migraines in the facial fracture cohort was 1.37-fold higher when compared with the comparison cohort (6.47 vs. 4.73 per 1000 person-years). There was a 1.31-fold risk of migraines in the adjusted hazard model and a 1.30-fold risk of migraines in the subdistribution hazard model (95% confidence interval [CI], 1.12-1.52 and 1.12-1.51, respectively). Malar/maxillary and nasal fractures showed 1.48- and 1.29-fold risks of migraines in the adjusted hazard model and subdistribution hazard model (95% CI, 1.16-1.89 and 1.05-1.59, respectively). There were no significant differences in migraine occurrence among patients who underwent surgery. Conclusions: Our findings indicated that malar/maxillary and nasal fractures were associated with a subsequent risk of migraines. There were no significant differences in migraine occurrence among patients who underwent surgery. Because of the retrospective nature of this study, further studies are warranted.

Preclinical evaluation of PEGylated liposomal doxorubicin as an effective radiosensitizer in chemoradiotherapy for lung cancer.

PURPOSE: Development of a safe and effective systemic chemotherapeutic agent for concurrent administration with definitive thoracic radiotherapy remains a major goal of lung cancer management. The synergistic effect of PEGylated liposomal doxorubicin and irradiation was evaluated in lung cancer cell lines both in vitro and in vivo. METHODS: In vitro radiosensitization of A549 and LLC cell lines was evaluated by colony formation assay, γH2AX fluorescent staining and western blot assay, and annexin V staining. A radiosensitization study with healthy human lung-derived cell line BEAS-2B was performed for comparative purposes. In vivo radiosensitization was evaluated by tumor ectopic growth, cell survival, pharmacokinetics, and biodistribution analyses. Cleaved caspase­3, the marker for apoptosis, was assessed immunohistochemically in A549 xenograft tumors. RESULTS: Treatment with PEGylated liposomal doxorubicin decreased A549 and LLC cell proliferation in a dose-dependent manner. In vitro studies revealed comparable radiosensitizer advantages of PEGylated liposomal doxorubicin and free doxorubicin, showing equivalent DNA double-strand breaks according to γH2AX fluorescent staining and western blot assays, similar numbers of apoptotic cells in the annexin­V staining assay, and moderately decreased clonogenic survival. In vivo studies demonstrated markedly slow ectopic tumor growth with prolonged survival following treatment with PEGylated liposomal doxorubicin plus irradiation in both A549 and LLC mouse models, suggesting that PEGylated liposomal doxorubicin is more effective as a radiosensitizer than free doxorubicin in vivo. Pharmacokinetics evaluation showed a longer half-life of approximately 40 h for PEGylated liposomal doxorubicin, confirming that the liposomal carrier achieved controlled release. Biodistribution evaluation of PEGylated liposomal doxorubicin confirmed high accumulation of doxorubicin in tumors, indicating the promising drug delivery attributes of PEGylated liposomal doxorubicin. Although free doxorubicin caused histopathologic myocarditis with the cardiac muscle fibers showing varying degrees of damage, PEGylated liposomal doxorubicin caused no such effects. The immunohistochemical expression of cleaved caspase-3-positive cells was greatest expressed in the irradiation and PEGylated liposomal doxorubicin combined treatment group, indicating prolonged tumoricidal effects. CONCLUSIONS: Our study provides preclinical in vitro and in vivo evidence of the effectiveness of PEGylated liposomal doxorubicin as a radiosensitizer, supporting its potential clinical development as a component of chemoradiotherapy.

Clinicopathological Association of Autophagy Related 5 Protein with Prognosis of Colorectal Cancer.

Gene mutation and pathogenesis bacteria are highly associated with colorectal cancer (CRC) development and progression. Autophagy is a self-clearance pathway to degrade abnormal proteins and infected bacteria in cells. Autophagy plays a dual role in cancer development. Among the autophagy-related (ATG) proteins, ATG5 is the key component required for the core machinery of autophagy. However, the role of ATG5 in CRC malignancy remains unclear. Herein, we found that a high ATG5 protein level was correlated with poor overall survival (OS) and disease-free survival (DFS) of 118 patients with CRC. After stratification with demographic and clinicopathologic factors, a high ATG5 protein level was significantly correlated with unfavorable overall survival in female and elder (>60 year) CRC patients and tumor tissues with poor differentiation, late T stages (III + IV), whereas the ATG5 protein level was positively associated with the overall survival in CRC patients without lymph node invasion and radiation therapy. In contrast, a high ATG5 protein level was significantly associated with worse DFS in CRC patients with early stage of AJCC and no radiation therapy. In addition, colorectal cancer cells stably harboring small interfering RNA (siRNA) against ATG5 diminished the tumorsphere formation and sensitized cancer cells to chemotherapeutic agents. Taken together, our results suggest that ATG5 might be a prognostic biomarker for CRC and a potential therapeutic target for CRC patients.

Randomized multi-reader evaluation of automated detection and segmentation of brain tumors in stereotactic radiosurgery with deep neural networks.

BACKGROUND: Stereotactic radiosurgery (SRS), a validated treatment for brain tumors, requires accurate tumor contouring. This manual segmentation process is time-consuming and prone to substantial inter-practitioner variability. Artificial intelligence (AI) with deep neural networks have increasingly been proposed for use in lesion detection and segmentation but have seldom been validated in a clinical setting. METHODS: We conducted a randomized, cross-modal, multi-reader, multispecialty, multi-case study to evaluate the impact of AI assistance on brain tumor SRS. A state-of-the-art auto-contouring algorithm built on multi-modality imaging and ensemble neural networks was integrated into the clinical workflow. Nine medical professionals contoured the same case series in two reader modes (assisted or unassisted) with a memory washout period of 6 weeks between each section. The case series consisted of 10 algorithm-unseen cases, including five cases of brain metastases, three of meningiomas, and two of acoustic neuromas. Among the nine readers, three experienced experts determined the ground truths of tumor contours. RESULTS: With the AI assistance, the inter-reader agreement significantly increased (Dice similarity coefficient [DSC] from 0.86 to 0.90, P < 0.001). Algorithm-assisted physicians demonstrated a higher sensitivity for lesion detection than unassisted physicians (91.3% vs 82.6%, P = .030). AI assistance improved contouring accuracy, with an average increase in DSC of 0.028, especially for physicians with less SRS experience (average DSC from 0.847 to 0.865, P = .002). In addition, AI assistance improved efficiency with a median of 30.8% time-saving. Less-experienced clinicians gained prominent improvement on contouring accuracy but less benefit in reduction of working hours. By contrast, SRS specialists had a relatively minor advantage in DSC, but greater time-saving with the aid of AI. CONCLUSIONS: Deep learning neural networks can be optimally utilized to improve accuracy and efficiency for the clinical workflow in brain tumor SRS.