Tuberculosis reactivation at ileum following immune checkpoint inhibition with pembrolizumab for metastatic nasopharyngeal carcinoma: a case report.

BACKGROUND: Tuberculosis (TB) reactivation has been increasingly identified following immune checkpoint inhibitor (ICI) therapy for cancer patients. However there has been no report on TB reactivation in the gastrointestinal tract. In the report, we describe a patient who developed TB ileitis after pembrolizumab for her metastatic nasopharyngeal carcinoma (NPC). Rechallenge with pembrolizumab after its temporary interruption together with anti-TB therapy produced continuous tumor response but without further TB reactivation. CASE PRESENTATION: A 29-year-old lady with metastatic NPC involving the cervical nodes, lungs and bones started pembrolizumab after failure to multiple lines of chemotherapy. She complained of sudden onset of abdominal pain, vomiting and bloody diarrhea with mucus 21 months after pembrolizumab. Colonoscopy revealed terminal ileitis with multiple caseating granulomas with Langerhan cells. Serum interferon gamma release assay was strongly positive. She was treated with anti-TB medication and was later rechallenged with pembrolizumab for her progressive lung metastases without further TB relapse while her lung metastases were brought under control again. CONCLUSION: To date, this is the first gastrointestinal TB reactivation after ICI therapy for cancer. Guidelines to screen for TB before initiation of ICIs in endemic areas should be established.

Radiomics in stereotactic body radiotherapy for non-small cell lung cancer: a systematic review and radiomic quality score study.

PURPOSE: Stereotactic body radiotherapy (SBRT) has been widely utilized for curative treatment of early-stage non-small cell lung cancer (NSCLC). It has achieved good local control rate comparable to surgery. Currently, no standard risk model exists for SBRT outcome or complication prediction. Radiomics has the potential to improve clinical outcome prognostication. Here, we reviewed the current literature on the radiomic analyses of thoracic SBRT through the use of radiomic quality score (RQS). MATERIALS AND METHODS: Literature search was conducted on PubMed and Embase to retrieve radiomics studies on SBRT for early NSCLC. The literature search included studies up to June 2021. Only full papers published in peer reviewed journals were included. Studies that included metastatic lung cancers or non-lung cancers were excluded. Two independent investigators evaluated each study using the RQS and resolved discrepancies through discussion. RESULTS: A total number of 25 studies were analysed. The mean RQS was 7.76 of a maximum score of 36. This corresponds to 21.56% of the maximum score. Lack of feature reduction strategies, external validation and open data sharing were identified as key limitations of the reviewed studies. Meanwhile, various common radiomic signatures across different studies such as gray level co-occurrence matrix Homogeneity and energy have been identified. Multiple robust radiomic models have also been reviewed that may improve outcome or complication prediction. CONCLUSION: Radiomics in thoracic SBRT has a very promising future as a prognostication tool. However, larger multicenter prospective studies are required to confirm radiomic signatures. Improvement in future study methodologies can also facilitate its wider application.

Computed tomography-based radiomic model predicts radiological response following stereotactic body radiation therapy in early-stage non-small-cell lung cancer and pulmonary oligo-metastases.

PURPOSE: Radiomic models elaborate geometric and texture features of tumors extracted from imaging to develop predictors for clinical outcomes. Stereotactic body radiation therapy (SBRT) has been increasingly applied in the ablative treatment of thoracic tumors. This study aims to identify predictors of treatment responses in patients affected by early stage non-small cell lung cancer (NSCLC) or pulmonary oligo-metastases treated with SBRT and to develop an accurate machine learning model to predict radiological response to SBRT. MATERIALS AND METHODS: Computed tomography (CT) images of 85 tumors (stage I-II NSCLC and pulmonary oligo-metastases) from 69 patients treated with SBRT were analyzed. Gross tumor volumes (GTV) were contoured on CT images. Patients that achieved complete response (CR) or partial response (PR) were defined as responders. One hundred ten radiomic features were extracted using PyRadiomics module based on the GTV. The association of features with response to SBRT was evaluated. A model using support vector machine (SVM) was then trained to predict response based solely on the extracted radiomics features. Receiver operating characteristic curves were constructed to evaluate model performance of the identified radiomic predictors. RESULTS: Sixty-nine patients receiving thoracic SBRT from 2008 to 2018 were retrospectively enrolled. Skewness and root mean squared were identified as radiomic predictors of response to SBRT. The SVM machine learning model developed had an accuracy of 74.8%. The area under curves for CR, PR, and non-responder prediction were 0.86 (95% confidence interval [CI], 0.794-0.921), 0.946 (95% CI, 0.873-0.978), and 0.857 (95% CI, 0.789-0.915), respectively. CONCLUSION: Radiomic analysis of pre-treatment CT scan is a promising tool that can predict tumor response to SBRT.

Immune-Related Endocrine Dysfunctions in Combined Modalities of Treatment: Real-World Data.

The number of immune-related endocrine dysfunctions (irEDs) has concurrently increased with the widespread use of immunotherapy in clinical practice and further expansion of the approved indications for immune checkpoint inhibitor (ICI) in cancer management. A retrospective analysis was conducted on consecutive patients ≥18 years of age with advanced solid malignancies who had received at least one dose of anti-programmed cell death protein 1 (anti-PD-1) and/or anti-CTLA4 antibodies between January 2014 and December 2019 at a university hospital in Hong Kong. Patients were reviewed up to two months after the last administration of an ICI. The types, onset times and grades of irEDs, including hypothyroidism, hyperthyroidism, adrenal insufficiency and immune-related diabetes mellitus, were recorded. Factors associated with irEDs were identified using multivariate analysis. A total of 953 patients (male: 603, 64.0%; median age: 62.0 years) were included. Of these, 580 patients (60.9%) used ICI-alone, 132 (13.9%) used dual-ICI, 187 (19.6%) used an ICI combined with chemotherapy (chemo + ICI), and 54 (5.70%) used immunotherapy with a targeted agent (targeted + ICI). A significantly higher proportion of patients using targeted + ICI had irEDs and hypothyroidism; in contrast, a higher proportion of patients using dual-ICI had adrenal insufficiency. There was no significant difference in the incidence of irED between the younger (<65 years) and older (≥65 years) patients. Using logistic regression, only treatment type was significantly associated with irEDs. Notably, older patients had a higher risk of having immune-related diabetes mellitus. This large, real-world cohort demonstrates that targeted + ICI has a higher risk of overall irED and hypothyroidism. Immunotherapy is safe and well-tolerated regardless of age, but close monitoring of fasting glucose is essential in older populations.

A Rare Case of Metastatic Primary Peritoneal Ependymoma: A Case Report and Literature Review.

BACKGROUND: Primary peritoneal ependymoma is an exceedingly rare tumour with only four cases reported in the literature. It typically follows an indolent disease course. We describe a rare case of metastatic primary peritoneal ependymoma which was treated with chemotherapy and radiotherapy resulting in prolonged survival to date for 10 years. Case Presentation. The patient was a 23-year-old female on presentation. She presented with right upper quadrant pain associated with an abdominal mass. Computed tomography demonstrated a large mass displacing the liver. Debulking surgery was done revealing a tumour arising from the peritoneum as well as multiple metastatic pleural and peritoneal nodules. Pathology was consistent with primary peritoneal ependymoma. The patient was then treated with multiple lines of chemotherapy containing etoposide as the backbone. She also received palliative radiotherapy to the thoracic metastases with good and durable response. CONCLUSION: We reported a rare case of metastatic primary peritoneal ependymoma. Etoposide containing the chemotherapy regimen is effective in the treatment of peritoneal ependymoma. Radiotherapy is also effective for palliation of local symptoms with durable response.

Plasticity of muscle synergies through fractionation and merging during development and training of human runners.

Complex motor commands for human locomotion are generated through the combination of motor modules representable as muscle synergies. Recent data have argued that muscle synergies are inborn or determined early in life, but development of the neuro-musculoskeletal system and acquisition of new skills may demand fine-tuning or reshaping of the early synergies. We seek to understand how locomotor synergies change during development and training by studying the synergies for running in preschoolers and diverse adults from sedentary subjects to elite marathoners, totaling 63 subjects assessed over 100 sessions. During development, synergies are fractionated into units with fewer muscles. As adults train to run, specific synergies coalesce to become merged synergies. Presences of specific synergy-merging patterns correlate with enhanced or reduced running efficiency. Fractionation and merging of muscle synergies may be a mechanism for modifying early motor modules (Nature) to accommodate the changing limb biomechanics and influences from sensorimotor training (Nurture).

Classification of runners' performance levels with concurrent prediction of biomechanical parameters using data from inertial measurement units.

Identification of runner's performance level is critical to coaching, performance enhancement and injury prevention. Machine learning techniques have been developed to measure biomechanical parameters with body-worn inertial measurement unit (IMU) sensors. However, a robust method to classify runners is still unavailable. In this paper, we developed two models to classify running performance and predict biomechanical parameters of 30 subjects. We named the models RunNet-CNN and RunNet-MLP based on their architectures: convolutional neural network (CNN) and multilayer perceptron (MLP), respectively. In addition, we examined two validation approaches, subject-wise (leave-one-subject-out) and record-wise. RunNet-MLP classified runner's performance levels with an overall accuracy of 97.1%. Our results also showed that RunNet-CNN outperformed RunNet-MLP and gradient boosting decision tree in predicting biomechanical parameters. RunNet-CNN showed good agreement (R2 > 0.9) with the ground-truth reference on biomechanical parameters. The prediction accuracy for the record-wise method was better than the subject-wise method regardless of biomechanical parameters or models. Our findings showed the viability of using IMUs to produce reliable prediction of runners' performance levels and biomechanical parameters.

Impulsivity in Hong Kong-Chinese club-drug users.

To investigate the relationship between personality, club-drug use and high-risk drug-related behaviour, 360 club-drug users and 303 non-drug users in Hong Kong were assessed on measures of two impulsivity dimensions, reward drive and rash impulsivity, and a related trait of punishment sensitivity. The most frequently used drugs were ketamine, ecstasy, and cannabis, with the majority of participants using two or more drugs on any one occasion. Club-drug users were more rash-impulsive and reward-driven, and less punishment-sensitive than non-drug users (p<0.001). Rash impulsivity, but not reward drive or punishment sensitivity, was significantly (p<0.001) associated with risky drug-related behaviour. There was no association between any personality traits and preferred drug. These findings suggest that, while those who use club drugs are generally more impulsive and less punishment-sensitive, some discrete facets of impulsivity are associated with differing patterns of drug-use behaviour.

Cough mixture abuse as a novel cause of folate deficiency: a prospective, community-based, controlled study.

Cough mixture abuse has been reported to cause severe folate deficiency and neurological defects. We carried out a prospective case-controlled survey to confirm this association and define the incidence and severity of the problem. A total of 57 cough mixture abusers and 47 other substance abusers (controls) were studied. When compared with controls, cough mixture abusers had a high incidence of low folate levels that could only be detected by screening.

Pain response in heroin users: personality, abstinence, and modulation by benzodiazepines.

We compared cold-pain responses among male current opioid users with and without concurrent benzodiazepine use, long-term ex-users, and healthy controls. Forty-eight current opioid users (14 concurrently using benzodiazepines), 34 ex-users (abstinent for ≥1 y) and 63 controls received cold-pressor tests. Pain threshold (first reporting pain) and pain tolerance (total immersion time) were recorded. Pain thresholds were similar in ex-users and current users; pain tolerance was similar in ex-users and controls. Net pain tolerance (endurance) in ex-users was intermediate between the other two groups. Current users showed higher pain threshold and shorter pain tolerance than controls (p<0.05). Current users not co-using benzodiazepines showed the lowest pain tolerance and net pain tolerance, and differed significantly from controls, ex-users, and current users co-using benzodiazepines (p<0.05). Neuroticism was higher in current users than in the other two groups (p<0.001), extraversion marginally lower (p<0.05); net pain tolerance differences remained significant after controlling for these. Benzodiazepine use modulates pain tolerance in opioid users. Pain responses altered by opioid use may partially recover with abstinence.

Capturing children's response to parental conflict and making use of it.

To read this article's abstract in both Spanish and Mandarin Chinese, please visit the article's full-text page on Wiley InterScience (http://interscience.wiley.com/journal/famp). The aim of our study is to examine the interface between children's physiological changes and the specificities of parental conflict, and to develop a procedure in which such information can be shared with the family for therapeutic change. Children from 20 families were exposed to parental conflict discussion (CD) while their arousals were measured through skin conductance and heart rate sensors. It was found that regardless of the subject of the argument, 80% of the time they were complaining about each other. Likewise, 80% of the time the children were responding to the parents' own interpersonal tension, including moments of silence. The protocol established for the study, consisting of CD and debriefing, was found to be a powerful tool in moving parents toward conflict resolution.

Dopamine receptor D4 gene -521C/T polymorphism is associated with opioid dependence through cold-pain responses.

Heroin users exhibit abnormal pain sensitivity called opioid-induced hyperalgesia that may weaken their determination to abstain. The dopamine receptor D4 gene (DRD4) is associated with heroin dependence; one of its polymorphisms is a C/T variation 521 bp upstream to the gene (-521C/T). We investigated whether this polymorphism was related to opioid dependence through modulation of cold-pain responses. We recruited 84 heroin-dependent Chinese male subjects and 168 healthy male Chinese controls. Genotyping was performed by PCR-RFLP. A significantly higher T allele frequency was observed in the heroin group (P= 0.041). Of the cohort recruited, 43 current heroin users and 66 controls were further subjected to a cold-pressor test (CPT) to determine their pain threshold and tolerance. TT controls demonstrated a significantly lower pain threshold than did their CC/CT counterparts (P= 0.022) and TT opioid users (P= 0.006). Moreover, CC/CT controls had a significantly higher pain tolerance than TT controls (P= 0.042) and CC/CT opioid users (P= 0.010). The data suggest that DRD4-521C/T plays an important role in opioid dependence through modulating cold-pain responses. TT individuals might have a higher tendency to use opioids because they experience pain less strongly after chronic opioid use.

Roadside detection of impairment under the influence of ketamine--evaluation of ketamine impairment symptoms with reference to its concentration in oral fluid and urine.

Although there are many roadside testing devices available for the screening of abused drugs, none of them can be used for the detection of ketamine, a popular abused drug in Hong Kong. In connection to local drug driving legislation, effective roadside detection of ketamine in suspected drug-impaired drivers has to be established. According to the drug evaluation and classification program (DEC), ketamine is classified in the phencyclidine (PCP) category. However, no study has been performed regarding the signs and symptoms exhibited by users under the influence of ketamine. In a study to develop a protocol for effective roadside detection of drug-impaired drivers, 62 volunteers exiting from discos were assessed using field impairment tests (FIT) that included measurements of three vital signs (i.e. body temperature, pulse rate and blood pressure), three eye examinations [pupil size, lack of convergence (LOC) and horizontal gaze nystagmus (HGN)] and four divided attention tests (Romberg, one-leg stand, finger-to-nose and walk-and-turn tests). Subsequent laboratory analysis of oral fluid and urine samples from the participants revealed the presence of common abused drugs in both the urine and oral fluid samples of 55 subjects. The remaining 7 subjects with no drug in their oral fluid samples were used as drug-free subjects. In addition, 10 volunteers from the laboratory who were regarded as drug-free subjects were also assessed using the same FIT. Among the 62 volunteers, 39 of them were detected with ketamine in their oral fluid. Of these ketamine users, 21 of them (54%) with only ketamine found in their oral fluid samples while the rest (18 subjects) of them had other drugs (i.e. MA, MDMA, benzodiazepines and/or THC) in addition to ketamine. Of the 21 ketamine-only users, 15 of them (71%) were successfully identified by FIT. It was found that when salivary ketamine concentrations were greater than 300 ng/mL, signs of impairment became evident, with over 90% detection rate using the FIT. By comparing the FIT observations on the 21 ketamine-only users with the drug-free subjects, the typical signs and symptoms observable for subjects under the influence of ketamine included LOC, HGN, elevated pulse rate and in general, failing the divided attention tests, especially the walk-and-turn and one-leg stand.