EUS-guided fiducial marker insertion for radiotherapy in advanced esophageal carcinoma: submucosal insertion may lead to less migration when compared to intratumoral insertion.

BACKGROUND: The use of radiotherapy is frequently required in the treatment of locally advanced esophageal squamous cell carcinoma. However, the margins of the tumor are often difficult to ascertain on computed tomography. Thus, EUS-guided fiducial marker insertion can aid the localization of the margins of the tumor. However, the optimal technique of the procedure is still uncertain. METHODS: This was a retrospective study of all patients that received EUS-guided fiducial marker insertion between March 2015 and December 2018. All patients suffering from esophageal squamous cell carcinoma scheduled for radiotherapy underwent the procedure within one week of the scheduled appointment. Gold fiducial markers were inserted under EUS guidance either intratumorally or within the submucosa just proximal and distal to the tumor. Outcome parameters included tumor characteristics, early and late migration rates, and tumor response rates. RESULTS: During the study period, 40 patients were recruited. 10 fiducial markers were placed intratumorally and 30 markers were placed submucosally. When comparing fiducials that were placed in the submucosa versus intratumorally, significantly more fiducials had early (40% vs 0%, RR = 0.6, 95% CI 0.36, 1.00) and late migration (60% vs 0%, RR = 0.33, 95% CI 0.13, 0.84) in the intratumoral group. The submucosal group had significantly more patients intended for curative intent (96.7% vs 70%, RR = 0.34, 95%CI 0.003, 0.361) and more patients with partial and complete response. There was no difference between the gross tumor volume, the clinical target volume, and the total radiation dose. CONCLUSION: In esophageal carcinomas planned for radiotherapy, fiducial markers placed in the submucosa may lead to less migration.

Post-transplantation primary central nervous system lymphoma in a patient with systemic lupus erythematosus and prolonged use of immunosuppressant.

Post-transplantation primary central nervous system lymphoma is an uncommon and fatal post-transplant lymphoproliferative disorder. Such lymphomas have been described in only a few case series in the literature. The incidence of this condition is rising with improved survival after organ transplantation. A case of post-transplantation primary central nervous system lymphoma in a young Chinese woman with systemic lupus erythematosus is described here. She presented with right-sided weakness and memory loss after tooth extraction 2 weeks before admission. Contrast computed tomography of the brain demonstrated a contrast rim-enhancing lesion over the left frontal lobe. With a history of recent dental procedure, long-term immunosuppressive therapy and computed tomography findings, cerebral abscess was highly suspected. Emergency operation was performed. Histopathology showed post-transplantation primary central nervous system lymphoma, with cells positive for B-cell marker CD20. Immunosuppressant was stopped and she was treated with radiotherapy and rituximab (anti-CD20 monoclonal antibody). She remained disease-free at 16 months. Post-transplantation primary central nervous system lymphoma is rare with variable presentation and radiological features. We believe rituximab may have a role in the treatment of such lymphomas.

Synergistic activities of Panobinostat and doxorubicin in soft tissue sarcomas.

BACKGROUND: Soft tissue sarcomas (STS) are rare diseases typically arising from connective tissues in children and adults. However, chemotherapies involved in the treatment of STS may cause toxic side effects and multi-drug chemoresistance, making the treatment even more challenging. Histone deacetylase inhibitors (HDACi) are epigenetic agents which have shown anti-tumor effects as single agent as well as combination use with other drugs. Our project intends to prove the same effects in STS. METHODS: Panobinostat (LBH589) plus doxorubicin was selected for investigations based on our previous research. Tumor xenografts were tried in an epithelioid sarcoma model to validate good synergy effects in vivo and a leiomyosarcoma model was used as a negative comparison group. Gene profile changes were studied afterwards. The possible pathway changes caused by HDACi were explored and validated by several assays. RESULTS: Synergy effect of LBH589 plus doxorubicin was successfully validated in STS cell lines and an epithelioid sarcoma mice model. We tried to reduce the dose of doxorubicin to a lower level and found the drug combination can still inhibit tumor size in mice. Furthermore, gene profile changes caused by LBH589 was studied by RNA-Sequencing analysis. Results showed LBH589 can exert effects on a group of target genes which can regulate potential biological functions especially in the cell cycle pathway.

Framework for Accurate Classification of Self-Reported Stress From Multisession Functional MRI Data of Veterans With Posttraumatic Stress.

Background: Posttraumatic stress disorder (PTSD) is a significant burden among combat Veterans returning from the wars in Iraq and Afghanistan. While empirically supported treatments have demonstrated reductions in PTSD symptomatology, there remains a need to improve treatment effectiveness. Functional magnetic resonance imaging (fMRI) neurofeedback has emerged as a possible treatment to ameliorate PTSD symptom severity. Virtual reality (VR) approaches have also shown promise in increasing treatment compliance and outcomes. To facilitate fMRI neurofeedback-associated therapies, it would be advantageous to accurately classify internal brain stress levels while Veterans are exposed to trauma-associated VR imagery. Methods: Across 2 sessions, we used fMRI to collect neural responses to trauma-associated VR-like stimuli among male combat Veterans with PTSD symptoms (N = 8). Veterans reported their self-perceived stress level on a scale from 1 to 8 every 15 s throughout the fMRI sessions. In our proposed framework, we precisely sample the fMRI data on cortical gray matter, blurring the data along the gray-matter manifold to reduce noise and dimensionality while preserving maximum neural information. Then, we independently applied 3 machine learning (ML) algorithms to this fMRI data collected across 2 sessions, separately for each Veteran, to build individualized ML models that predicted their internal brain states (self-reported stress responses). Results: We accurately classified the 8-class self-reported stress responses with a mean (± standard error) root mean square error of 0.6 (± 0.1) across all Veterans using the best ML approach. Conclusions: The findings demonstrate the predictive ability of ML algorithms applied to whole-brain cortical fMRI data collected during individual Veteran sessions. The framework we have developed to preprocess whole-brain cortical fMRI data and train ML models across sessions would provide a valuable tool to enable individualized real-time fMRI neurofeedback during VR-like exposure therapy for PTSD.

Patterns of care and survival of Chinese glioblastoma patients in the temozolomide era: a Hong Kong population-level analysis over a 14-year period.

Background: The aim of this study is to address the paucity of epidemiological data regarding the characteristics, treatment patterns and survival outcomes of Chinese glioblastoma patients. Methods: This was a population-level study of Hong Kong adult (>18 years) Chinese patients with newly diagnosed histologically confirmed glioblastoma between 2006 and 2019. The age standardized incidence rate (ASIR), patient-, tumor- treatment-related characteristics, overall survival (OS) as well as its predictors were determined. Results: One thousand and ten patients with a median follow-up of 10.0 months were reviewed. The ASIR of glioblastoma was 1.0 per 100 000 population with no significant change during the study period. The mean age was 57 + 14 years. The median OS was 10.6 months (IQR: 5.2-18.4). Independent predictors for survival were: Karnofsky performance score >80 (adjusted OR: 0.8; 95% CI: 0.6-0.9), IDH-1 mutant (aOR: 0.7; 95% CI: 0.5-0.9) or MGMT methylated (aOR: 0.7; 95% CI: 0.5-0.8) glioblastomas, gross total resection (aOR: 0.8; 95% CI: 0.5-0.8) and temozolomide chemoradiotherapy (aOR 0.4; 95% CI: 0.3-0.6). Despite the significant increased administration of temozolomide chemoradiotherapy from 39% (127/326) of patients in 2006-2010 to 63% (227/356) in 2015-2019 (P-value < .001), median OS did not improve (2006-2010: 10.3 months vs 2015-2019: 11.8 months) (OR: 1.1; 95% CI: 0.9-1.3). Conclusions: The incidence of glioblastoma in the Chinese general population is low. We charted the development of neuro-oncological care of glioblastoma patients in Hong Kong during the temozolomide era. Although there was an increased adoption of temozolomide chemoradiotherapy, a corresponding improvement in survival was not observed.

Prevalence and prognostic impact of comorbidities and peripheral blood indices in sarcomas.

BACKGROUND: The prognostic impact of comorbidities in patients with sarcomas is not well defined. The aims of this study were to examine the implications of comorbidities and abnormal peripheral blood indices in patients with sarcomas. METHODS: A population-based database was assembled to extract patients with sarcoma in Hong Kong between January 2004 and March 2018. Charlson's Comorbidity Index (CCI) score and prevalence of comorbidities, neutrophil, lymphocyte and platelet counts at diagnosis were assessed. The prognostic values of CCI, neutrophil-lymphocyte (NLR) and platelet-lymphocyte ratios (PLR) were estimated using Cox proportional hazard models. Restricted cubic spline plots were used to explore the association of baseline NLR and PLR with all-cause and cancer-specific mortality. RESULTS: Among 3358 eligible patients with sarcomas, 52.2% died after a median 26 months of follow-up. The most common comorbidities were diabetes mellitus (9.8%) and cerebrovascular disease (4.8%). Patients with higher CCI had higher mortality (CCI=3 vs CCI=2; HR 1.49; 95% CI 1.19 to 1.87; p<0.01; CCI ≥7 vs CCI =2; HR 3.20; 95% CI 2.62 to 3.92; p<0.001). Abnormal NLR and PLR levels were associated with higher all-cause mortality (NLR: HR 1.698, p<0.001, 95% CI 1.424 to 2.025; PLR: HR 1.346, p<0.001, 95% CI 1.164 to 1.555) and cancer-related mortality (NLR: HR 1.648, p<0.001, 95% CI 1.341 to 2.024; PLR: HR 1.430, p<0.001, 95% CI 1.205 to 1.697). CONCLUSIONS: This is the largest population-based soft-tissue or bone sarcoma cohort worldwide. Comorbidities have significant negative prognostic impact on the survival of patients with sarcomas. Moreover, NLR and PLR are robust prognostic factors, and abnormal NLR and PLR have negative effects yet non-linear effects on survival.

A randomized study of olanzapine-containing versus standard antiemetic regimens for the prevention of chemotherapy-induced nausea and vomiting in Chinese breast cancer patients.

OBJECTIVES: Chemotherapy-induced nausea and vomiting (CINV) are distressing symptoms. This randomized study evaluated the antiemetic efficacies of standard antiemetic regimen with/without olanzapine. PATIENTS AND METHODS: Eligible patients were chemotherapy-naive Chinese breast cancer patients who were planned for (neo)adjuvant doxorubicin/cyclophosphamide. Antiemetic regimen for all studied population included aprepitant, ondansetron and dexamethasone; patients were randomized to Olanzapine (with olanzapine) or Standard arms (without olanzapine). Patients filled in self-reported diaries and completed visual analogue scales for nausea, as well as Functional Living Index-Emesis questionnaires. Blood profiles including fasting glucose and lipids were monitored. RESULTS: 120 patients were randomized. In Cycle 1 doxorubicin/cyclophosphamide, the Olanzapine arm had significantly higher rates of "Complete Response" than the Standard arm: 65.0% vs 38.3% in the overall period (p = 0.0035), 70.0% vs 51.7% in the acute period (p = 0.0397) and 92.9% vs 74.2% in the delayed period (p = 0.0254). Olanzapine arm also had significantly higher rates of "No significant nausea" and "No nausea" during all 3 time-frames and better QOL. Similar findings were also revealed throughout multiple cycles. Pre-study abnormalities in glucose and lipids occurred in 39.7% and 34.2% of the studied population respectively; there were no differences in these parameters between the two arms at end-of-study assessment. CONCLUSION: The addition of olanzapine to standard aprepitant-based antiemetic regimen provides clinically meaningful improvement in controlling CINV. This was associated with a positive impact on QOL and tolerable toxicity profiles among Chinese breast cancer patients receiving doxorubicin/cyclophosphamide chemotherapy. Further studies on metabolic profiles of breast cancer patients are warranted.

Airway inflammatory and spirometric measurements in obese children.

OBJECTIVES: To investigate the association between obesity and airway inflammation and spirometric parameters in local children. DESIGN: Cross-sectional and observational study. SETTING: Paediatric clinics of a university-affiliated teaching hospital in Hong Kong. PATIENTS: Chinese subjects aged 6 to 18 years were recruited from the paediatric clinics. Obesity was defined as being 120% or more of the median weight-for-height. MAIN OUTCOME MEASURES: Airway inflammation assessed by exhaled nitric oxide concentration; lung function evaluated by measuring forced expiratory flow in 1-second and forced vital capacity using spirometry; and peak expiratory flow rate measured by using a mini-Wright peak flow meter. RESULTS: Fifty-five subjects were recruited into four groups as follows: 13 non-obese controls, 16 obese non-asthmatics, 15 non-obese asthmatics, and 11 obese asthmatics. The median (interquartile range) exhaled nitric oxide concentrations of these groups were 17.6 (14.4-20.9), 33.3 (26.1-75.4), 65.7 (32.0-110.0) and 49.2 (41.1-82.6) parts per billion, respectively (P=0.001 for trend). Post-hoc analysis revealed higher exhaled nitric oxide concentration in the latter three groups (obese and/or asthmatic subjects) than controls (P< or =0.002). Exhaled nitric oxide concentration did not differ among obese non-asthmatics, non-obese asthmatics, and obese asthmatics (P>0.1 for all). In non-asthmatics, exhaled nitric oxide concentration correlated positively with age (P=0.048), weight-for-height z-score (P=0.001), and forced vital capacity (P=0.009). Weight-for-height z-score correlated positively with forced vital capacity (P=0.041), but inversely with the forced expiratory flow in 1-second/forced vital capacity ratio (P=0.049). Such correlations were not observed in asthmatic children. CONCLUSION: Increased airway inflammation as revealed by exhaled nitric oxide concentration was found in obese non-asthmatic children. Weight-for-height z-score as an indicator of childhood obesity correlated with exhaled nitric oxide concentration and spirometric parameters in children without asthma. Nonetheless, concomitant obesity does not influence exhaled nitric oxide concentration in asthmatic children. Further studies are needed to identify the pathophysiologic mechanisms for such associations.

Determining a cut-off residual tumor volume threshold for patients with newly diagnosed glioblastoma treated with temozolomide chemoradiotherapy: A multicenter cohort study.

Standard-of-care treatment of glioblastomas involves maximal safe resection and adjuvant temozolomide chemo-radiotherapy. Although extent of resection (EOR) is a well-known surgical predictor for overall survival most lesions cannot be completely resected. We hypothesize that in the event of incomplete resection, residual tumor volume (RTV) may be a more significant predictor than EOR. This was a multicenter retrospective review of 147 adult glioblastoma patients (mean age 53 years) that underwent standard treatment. Semiautomatic magnetic resonance imaging segmentation was performed for pre- and postoperative scans for volumetric analysis. Cox proportional hazards regression and Kaplan-Meier survival analyses were performed for prognostic factors including: age, Karnofsky performance score (KPS), O(6)-methylguanine methyltransferase (MGMT) promoter methylation status, EOR and RTV. EOR and RTV cut-off values for improved OS were determined and internally validated by receiver operator characteristic (ROC) analysis for 12-month overall survival. Half of the tumors had MGMT promoter methylation (77, 52%). The median tumor volume, EOR and RTV were 43.20 cc, 93.5%, and 3.80 cc respectively. Gross total resection was achieved in 52 patients (35%). Cox proportional hazards regression, ROC and maximum Youden index analyses for RTV and EOR showed that a cut-off value of <3.50 cc (HR 0.69; 95% CI 0.48-0.98) and ≥84% (HR 0.64; 95% CI 0.43-0.96) respectively conferred an overall survival advantage. Independent overall survival predictors were MGMT promoter methylation (adjusted HR 0.35; 95% CI 0.23-0.55) and a RTV of <3.50 cc (adjusted HR 0.53; 95% CI 0.29-0.95), but not EOR for incompletely resected glioblastomas.

Controversies and consensus of neoadjuvant chemotherapy in soft-tissue sarcomas.

Together with surgery and radiotherapy, systemic treatment with cytotoxic chemotherapy and molecular targeted agents is one of the main therapeutic pillars in the treatment of soft-tissue sarcomas and is the mainstay of treatment in patients with advanced or metastatic disease. Unlike other more common malignancies such as breast and colorectal cancer, the role of chemotherapy when used in the adjuvant setting in soft-tissue sarcomas is less well defined. Results from prior studies have been conflicting, in part due to the heterogeneity and rarity of the disease, and large-scale meta-analysis has been performed to address this issue. Neoadjuvant chemotherapy, defined as the use of chemotherapy before definitive treatment with surgery or radiotherapy, has distinct theoretical and practical advantages, which can potentially be beneficial to the patient. However, the currently available evidence to support its use is even more scarce. In this review article, we describe the current established data behind the use of adjuvant chemotherapy in selected patients with localised soft-tissue sarcomas and, through extrapolation of available data, discuss the potential role of it when used in the upfront setting.

Computed tomography interobserver agreement in the assessment of aneurysmal subarachnoid hemorrhage and predictors for clinical outcome.

BACKGROUND: The severity of aneurysmal subarachnoid hemorrhage (SAH) is often assessed by the clinical state of the patient on presentation, but radiological evaluation of the extent of hemorrhage has rarely been examined in the literature. Several CT scan based grading systems exist yet only a few studies have investigated interobserver agreement. We evaluated five radiological grading systems and assessed their clinical value for early prognostication. METHODOLOGY: This was a retrospective study of patients diagnosed with aneurysmal SAH with a CT scan performed within 72 hours of symptom onset. Four independent observers, blinded to patient outcome, evaluated each scan using the five grading systems. A separate assessor determined 6 month outcome from clinical records. The primary outcome was interobserver agreement for each grading system using the Fleiss κ statistic. The secondary endpoint was the 6 month modified Rankin Scale score, with poor outcome defined as a score of 4-6. RESULTS: 165 patients with a mean age of 59 years were assessed. Interobserver agreement for the Fisher, modified Fisher, Claassen, Barrow Neurological Institute, and Hijdra grading systems were as follows: k=0.53 (moderate), k=0.42 (moderate), k=0.38 (mild), k=0.20 (poor), and k=0.66 (good), respectively. The only independent clinical risk factor for poor outcome was a World Federation of Neurological Surgeons (WFNS) grade of 4 or 5 (adjusted OR 6.55; p<0.05). After adjusting for confounders, Fisher grade 4 (adjusted OR 17.84), modified Fisher grade 4 (adjusted OR 5.65), and Hijdra grade 3 (adjusted OR 3.34) were associated with poor outcome. Receiver operator characteristic analysis revealed that the Hijdra grading system (area under the curve=0.76) was more predictive of outcome compared with the Fisher and modified Fisher systems. A Hijdra cut-off score of 22 was associated with poor outcome (adjusted OR 5.92). CONCLUSIONS: The Hijdra grading system had the best interobserver agreement and was a better independent early predictor for 6 month clinical outcome than the other systems. A Hijdra score ≥22 was associated with poor outcome.

Paediatric burn prevention: an epidemiological approach.

OBJECTIVE: To study the mechanism of burn in hospitalized paediatric burn patients in order to develop a focused burn prevention campaign. METHODS: Acute paediatric burn patients were identified from the unit admission records. Detailed medical records were reviewed to identify the key demographic and management information including the country of residence, age, gender, extent of injury, specific treatment and hospital stay. Parents were then contacted to provide detailed information about the mechanism of the accident, first aid given, living density and parent's educational level. RESULTS: Two hundred and eighty-four admissions were identified in a 5-year period. Two hundred and twenty-four of these patients came from a defined regional population served by the hospital. The median age of patients was 3 and male to female ratio 1:0.74. The most common age group for burns was 1-2 years. The most common type of burns were scalds. Domestic burns accounted for 84.7% of admissions. Median burn area was 4% of the total body surface area with a range of 0.2-45%. Fifty percent of patients had no first aid treatment prior to presentation at the hospital. More accidents happened in homes with a high living density and the majority of parents had both completed secondary education. The most dangerous location in the house was the living room, followed by the bathroom, kitchen then bedroom. The majority of burns were related to hot drinks, followed by hot food and then bathing. CONCLUSION: Detailed investigation of burn incidents can reveal repeated mechanisms of injury, which direct the focus of preventive strategies.

A Novel Experimental and Analytical Approach to the Multimodal Neural Decoding of Intent During Social Interaction in Freely-behaving Human Infants.

Understanding typical and atypical development remains one of the fundamental questions in developmental human neuroscience. Traditionally, experimental paradigms and analysis tools have been limited to constrained laboratory tasks and contexts due to technical limitations imposed by the available set of measuring and analysis techniques and the age of the subjects. These limitations severely limit the study of developmental neural dynamics and associated neural networks engaged in cognition, perception and action in infants performing "in action and in context". This protocol presents a novel approach to study infants and young children as they freely organize their own behavior, and its consequences in a complex, partly unpredictable and highly dynamic environment. The proposed methodology integrates synchronized high-density active scalp electroencephalography (EEG), inertial measurement units (IMUs), video recording and behavioral analysis to capture brain activity and movement non-invasively in freely-behaving infants. This setup allows for the study of neural network dynamics in the developing brain, in action and context, as these networks are recruited during goal-oriented, exploration and social interaction tasks.

Decoding of intentional actions from scalp electroencephalography (EEG) in freely-behaving infants.

The mirror neuron system (MNS) in humans is thought to enable an individual's understanding of the meaning of actions performed by others and the potential imitation and learning of those actions. In humans, electroencephalographic (EEG) changes in sensorimotor a-band at central electrodes, which desynchronizes both during execution and observation of goal-directed actions (i.e., µ suppression), have been considered an analog to MNS function. However, methodological and developmental issues, as well as the nature of generalized µ suppression to imagined, observed, and performed actions, have yet to provide a mechanistic relationship between EEG µ-rhythm and MNS function, and the extent to which EEG can be used to infer intent during MNS tasks remains unknown. In this study we present a novel methodology using active EEG and inertial sensors to record brain activity and behavioral actions from freely-behaving infants during exploration, imitation, attentive rest, pointing, reaching and grasping, and interaction with an actor. We used 5-band (1-4Hz) EEG as input to a dimensionality reduction algorithm (locality-preserving Fisher's discriminant analysis, LFDA) followed by a neural classifier (Gaussian mixture models, GMMs) to decode the each MNS task performed by freely-behaving 6-24 month old infants during interaction with an adult actor. Here, we present results from a 20-month male infant to illustrate our approach and show the feasibility of EEG-based classification of freely occurring MNS behaviors displayed by an infant. These results, which provide an alternative to the µ-rhythm theory of MNS function, indicate the informative nature of EEG in relation to intentionality (goal) for MNS tasks which may support action-understanding and thus bear implications for advancing the understanding of MNS function.